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.

CLINICAL REPORTS Pa tient 1 The proposita K P (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-trimester 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 a n 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 KEY WORDS: popliteal pterygium, cleft lip/ the midpoint of the lids to the temporal margins (Fig. 2). palate, ankyloblepharon, lip She had a right cleft lip, lower lip pits, a complete cleft pits, syndactyly, autosomalpalate, and multiple oral synechiae, which included a dominant inheritance 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 nuINTRODUCTION chal skin. There were no cardiovascular or abdominal Trelat 118691 is generally credited with the first de- anomalies. There was mild intracrural webbing and hyscription of the popliteal pterygium syndrome (PPS). poplasia of the labia majora (Fig. 3 ) . Popliteal webbing More than 60 cases have since been reported. The syn- was more marked on the right (Fig. 4). Variable skin drome is characterized by marked variability in expres- syndactyly involved the 3rd and 4th fingers of both sion, while the occasional family history suggests the hands (Fig. 51, the 4th and 5th toes of both feet, and the possibility of lack of penetrance [Kind, 19701. We have 2nd and 3rd toes of the left foot (Fig. 6D). There was ascertained a family through a severely affected child marked dimpling over the elbows and knees. The oral and ocular synechiae were severed a t 3 days; and her less affected mother. Family history showed several other apparently mildly manifesting gene car- the cleft lip repaired a t 6 months and the palate a t 14 riers. Evidence was sought as to whether sporadic cases months. Active physiotherapy resulted in eventual full represent new mutations of the autosomal-dominant extension of both legs. Psychomotor development has PPS or are a closely related genocopy. The name pop- been normal; some delay in speech noted a t 15 months h e a l pterygium is used in preference to popliteal web was attributed to chronic otitis media, for which myrsimply to avoid confusion that might occur with the ingotomy tubes were inserted. There was some early delay in weight gain. abbreviation PWS and Prader-Willi syndrome. 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.

Received for publication April 11,1989;revision received August 25, 1989. Address reprint requests to Alasdair Hunter, Division of Genetics, Children’s Hospital of Eastern Ontario Ottawa, Ontario. Canada K1H 8L1.

o 1990 Wiley-Liss, Inc.

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

9.” I

41,

A

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

IV 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.

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 cutaneous 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 cutaneous 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.

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

excess gingival frenula, lateral deviation of the great toes, a n 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.

Popliteal Pterygium Syndrome mal, although there was some question as to the interpretation 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 [Kopits, 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. Generally, 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 tenatively 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 involve 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

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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 facilitate distinction from a number of other syndromes that may have associatedjoint webs [Hall et al., 1982; Happle et al., 1980; Herrmann e t 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 facilitate 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 counseling 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 personal communication to Long and Blandsford [ 19621, reported that a patient in his family, which was reviewed by Van der Woude a s a n example of the cleftingl lower lip-pit syndrome, also had ankyloblepharon. A similar case reported by Oberst [19101 is cited by Cervenka 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 combinations 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 difficult. 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. Further cases were reported by Spiegel and Colton [1985]. The Hay-Wells syndrome shares many characteristics

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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, hyperpigmented 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 lacrimoauriculo-dental-digital [Hollister et al., 19731 syndromes bear some resemblance to these former 2 conditions, Ankyloblepharon in association with curly hair and hypoplastic (not truly dysplastic) nails was reported as the apparently autosomal-dominant curly hairankyloblepharon-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 a n 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 cleftpalate lateral oral synechiae (CPLS) syndrome [Fuhrmann 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. R e u s et al. [19741commented on a particular face in the syndrome. None of these syndromes discussed include the combination 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 Berauds [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 introducing 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 [Escobar 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 a s 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 a n 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

Popliteal Pterygium Syndrome 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 preaxial 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 character for the PPS syndrome. (See Appendix A.) Two issues that have been addressed to varying degrees 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 complicate 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 excluding 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, a s 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 systematic 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 a s a group are still likely to be biased

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toward greater severity because of the requirement to ascertain a propositus. Thus, a comparison that eliminates 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 probandlnonproband comparison might result in a n 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 examinations of all close relatives of patients with PPS, will be of interest and may provide a solution to the genetic counseling problems posed by the presence of findings such a s 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 a n elevated mean paternal age of 34 years. If the families described by Escobar and Weaver [ 19781are 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 a n equally important determinant 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.

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Hunter TABLE I. Syndrome Manifestations*

Comparison

groups

.

~~~

Number cases

Number families

Ankyloblepharon

Cleft lipipal ~~~

Lip _ _pits-~

1959 and before 1960 and after Surgical Non-surgical

15 53 34 34

12 31 24 19

2/15(13) 19/53(36) 11134(32) 10/34(29)

11/15(78) 50/53(94) 29/34(85) 32/34(94)

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

32 40 28 44 44 28 12 12

23 30 44 16 12 7

10/32(31) 12/40(30) 12128(43) 10/44(23) 19/44(43) 3/28(11) 1/12(8) 3/12(25)

15132(47) 27132i84) 36140(90) 19140i48) 23/28(82) 13/28(46) 21/44(48) 40/44(91) 37/44(84) 22144i50) 26/28(93) 12/28(43) 11/12(92) 5/12(42) 12/12(100) 4/12(33)

11

7

5/11(45)

Popliteal web

Number’ 54

Crural web 8/54(15)

No popliteal web

17

0.17(0)

10111(90)

Syngnathia

~~

4/15(27) 2/15(18) 29/53(55) 28153i53) 13/34(38) 15/34(44) 20/34(59) 16/34(47)

7/11(63)

Hand syndact

Popliteal web 14/15(93) 38/53(72) 27/34(79) 25/34(74)

10/32(31) 23/40(58) 14/28(50) 19/44(43) 24/44(55) 9128(32) 4/12(33) 4/12i33) 8/11(72)

Hand absence __

5115i33) 6/53(11) 6/34(18) 5/34(15)

2/15(18) 4/53(8) 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)

7/11(63)

Genital anomaly 32/54(59) 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] carried 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 muscles, nerves, arteries, and bone, but considered the unexplained muscle shortness, particularly that of the semitendinosus, 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 prominent 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 a n hypothesis that localized development of abnormal and “leaky” vessels leads to edema, which secondarily 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 ligaments 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 ultimately 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

Popliteal Pterygium Syndrome

Toe

Toe

Toe-skin

_syndact _ _ _ _ absence ~ _ _ _ _p y_r a_m i~ d

Hypopl nails

Cryptorchid

1/7(14) 4123(17) 1/14(7) 4/16(25)

8/15(53) 28/53(53) 16/34(47) 18/34(53)

3/15(20) 14/53(26) 6/34(18) 11/34(32)

1/15(7) 16/53(30) 8/34(24) 10/34(29)

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

8/32(25) 10/40(25) 9/28(32) 9/44(20) 11/44(25) 7/28(25) 2/12(17)

8/32(25) 10/40(25) 9/28(32) 9/44(20) 15/44(34) 3/28(11) 2/12(17)

5/12(42)

1/12(8)

8/11(72)

3/11(27)

Scrotum

Penis

Labia

abn 2/7(28) 7/23(30) 6/14(43) 3/16(19)

abn

abn

1/7(14) 1123(4) 1/14(7) 1/16(6)

203

4/8(50) 15/30(50) 8/20(40) 12/18(67)

Clitoromeg 3/8(38) 9130(3O) 5/20(25) 4/18(22)

9/16(56) 10/23(43) 15/27(56) 5/13(38) 3/5(60)

3/16(19) 5/23(22) 6/27(22) 3/13(23) 1/5(20)

4/28(14) 4/44(9) 5/44(11) 3/13(28) 2/12(17)

Genital

Crural web-

0 /8 (0 ) 7153(13) 3/34(9) 4/34(12) 3/32(9) 5/40(13)

5/12(42) 0/20(0) 5/17(29) 0/15(0) 0/7(0)

9/32(28) 22/40(55) 5/12(42) 2/12(17) 4/20(25) 0/20(0) 8/17(47) 2/17(12) 1/15(7) 0/15(0) 0/7(0) 0/7(0)

3/12(25)

0/7(0)

2/7(29)

0/7(0)

3/5(60)

1/5(20)

1/12(8)

2/11(18)

0/3(0)

1/3(33)

0/3(3)

4/8(50)

1/8(13)

1/11(9)

scar from the back to the sternum is reminiscent of a n 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-stageembryo [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 a n epithelial abnormality or failure of programmed cell death. Further studies of the type reported by Fitch e t 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. REFERENCES Aberle-Horstenegg W (19371: Flughautbildung zwischen Ober- und Unterschenkel mit abnormer Muskelbildung (M. Ischio-suralisl. Z Orthop Grenz 6616721-29. Audino G, Teconi R, Clementi M, Saia OS, Cordioli GP (1984):Popliteal pterygium syndrome presenting with orofacial abnormalities. J Max Fac Surg 12174-177. Bajaj PS, Bailey BN (1969):Ectopic scrotum: A case report. Br J Plast Surg 22:87-89. Bartsocas CS, Papas CV (1972):Popliteal pterygium syndrome. J Med Genet 9:222-226. Basch K (18911: Uber sogenannte Flughautbildung beim Menschen. 2 Heilkunde 12:499-515. Basch K (18921:Ein weiterer Fall von sog. Flaghautbildung. Prag Med Wochenschr 17:289-291. Baughman FA (1971): CHANDS The curly hair-ankyloblepharonnail dysplasia syndrome. In Bergsma D (ed):“The Clinical Deliniation of Birth Defects (XII), Skin, Hair and Nails.” Baltimore: Williams & Wilkins Co., for the National Foundation-March of Dimes, BD:OAS VII(8):100-102. Berauds [18611: Cited by Cervenka et al. (1967). Bixler D, Poland C , Nance W (19731: Phenotypic variation in popliteal pterygium syndrome. Clin Genet 4:220-228.

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Hunter

Bowen P, Armstrong HB (1976):Ectodermal dysplasia, mental retardation, cleft lipipalate and other anomaliesin three sibs. Clin Genet 9:35-42. Carnevale A, Hernandez AL, De Los Cobos VL (1973): Sindrome de pterigium familiar con probable transmision dominante ligada a1 chromosoma X. Rev Invest Clin 25:237-244. Cervenka J , Gorlin RJ, Anderson VE (1967): The syndrome of pits of the lower lip and cleft lip and/or palate. Am J Hum Genet 19:416-432. Champion R, Cregan J C F (1959): Congenital popliteal webbing in siblings. J Bone Joint Surg 41B:355-357. Cheirif S, Grayson BH, Maccaro HA (1985): Bartsocas-Papas syndrome. NY State Dent J 51:lOl-102. Chen H, Chang C, Mirsa R, Peters H , Grijalva N, Opitz J M (1980): Multiple pterygium syndronie. Am J Med Genet 7:91-102. Dahmen G (1962): Uber die Versorgung einer doppelseitigen Kniestreckhemmung wegen Fliigelfell mit einem provisorischen Knie-Ruhebein. Z Orthop 95:112-113. Deskin RW, Sawyer DG (1988): Popliteal pterygium syndrome. Int J Ped Otorhinolaryngol 15:17-22. Escobar V, Weaver D (1978): Popliteal pterygium syndrome. A phenotypic and genetic analysis. J Med Genet 15:35-42. Fevre M, Languepin A (1962): Les brides cruro-jambieres contenant le nerf sciatique. Le syndrome bride poplitee e t malformations multiples. Presse Med 70:615-618. Fischer H (1893):Ein Fall von sogenannter Flughautbildung zwischen Ober- und Unterschenkel. Prag Med Wochenschr 18:579-581. Fitch N, Rochon L, Srolovitz H, Hamilton E (1985):Vascular abnormalities in a fetus with multiple pterygia. Am J Med Genet 21:755-760. Frias JL, Holahan JR, Rosenbloom AL, Felman AH (1973):An autosoma1 dominant syndrome of multiple pterygium, ptosis and skeletal abnormalities. Presented a t the Fourth International Conference on Birth Defects. Exerpta Medica, Int. Cong Series 29:19 (abst). Frohlich GS, Starzer KL, Tortora J M (1977):Popliteal pterygium syndrome: Report of a family. J Pediatr 90:91-93. Fuhrmann W, Koch F, Schweckendiek W (1972):Autosomal dominante Vererbung von Gaumenspalte und Synechien zwischen Gaumen und Mundboden oder Zunge. Humangenetik 14:196-203. Gassner I, Muller W, Rossler H, Kofler J, Mitterstieler G (1979):Familial occurrence of syngnathia congenita syndrome. Clin Genet 15:241-244. Gorlin R J , Psaume J (1962): Orofacial dysostosis: A new syndrome. A study of 22 cases. J Pediatr 61:520-530. Gorlin RJ, Sedano HO, Cervenka J (1968): Popliteal pterygium syndrome: Syndrome comprising cleft lip-palate, popliteal and intracrural pterygia, digital and genital anomalies. Pediatrics 41:503-509. Hackenbroch M (1924): Ueber einen Fall von kongenitaler Kontraktur der Kniegelenke mit Flughautbildung. Z Orthop Chir 38:508-524. Hall J G (1984): Editorial comment: The lethal multiple pterygium syndromes. Am J Med Genet 17:803-807. Hall JG, Reed SD, Rosenbaum KN, Gershanik, Chen H , Wilson KM (1982):Limb pterygium syndromes: A review and report of eleven patients. Am J Med Genet 12:377-409. Hamamoto J , Matsumoto T (1984): A case of facio-genito-popliteal syndrome. Ann Plast Surg 13:224-229. Hansson LI, Hansson V, Jonsson K (1976): Popliteal pterygium syndrome in a 74-year-old woman. Acta Orthop Scand 47:525-533. Happle R, Koch H , Lenz W (1980): The CHILD syndrome: Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. E u r J Pediatr 134:27-33. Hartwig NG, Vermeij-Keers Chr, Bruijn JA, van Groningen K, Ottervanger HP, Holm JP (1989): Case of lethal multiple pterygium syndrome with special reference to the origin of pterygia, Am J Med Genet 33537-541. Hay RJ, Wells RS (1976): The syndrome of ankyloblepharon, ectoderma1 defects, and cleft lip and palate. Br J Dermatol 94:277-289. Hecht F, Jarvinen J M (1967): Heritable dysmorphic syndrome with normal intelligence. J Pediatr 70:927-935. Herold HZ, Shmueli G, Baruchin AM (1986):Popliteal pterygium syndrome. Clin Orthop Re1 Res 209:194-197.

Herrmann J, Pallister PD, Opitz J M (1969):Craniostenosis syndromes. Rocky Mt Med J 66:45-56. Hirakawa M, Kojima T, Kumagai K, Kita A (1984): A case of the popliteal pterygium syndrome. J p n J Plast Reconstr Surg 27:423-428. Hollister DW, Klein SH, De Jager H J , Lachman RS, Rimoin DL (1973): The lacrimo-auriculo-dento-digitalsyndrome. J Pediatr 83:438-444. Hunter AGW, Carpenter BF (1986):Implications of malformations not due to amniotic bands in the amniotic band syndrome. Am J Med Genet 24:691-700. Jones KL (1988):Escobar syndrome (multiple pterygium syndrome). In Jones KL (ed.) “Smith‘s Recognizable Patterns of Human Malformations.” 4th ed. Philadelphia: W. B. Saunders, pp 264-265. Khan SN, Hufnagle KG, Pool R (1986): Intrafamilial variability of popliteal pterygium syndrome: A family description. Cleft Palate J 23:233-236. Kind H P (1970): Popliteales pterygiumsyndrom. Helv Acta Paediatr 5:508-516. Klein D (1962):Un curieux syndrome hereditaire: Cheilopalatoschisis avec fistules de la levre inferieure associe a une syndactylie, une onychodysplasie particuliere, un pterygion poplite unilateral e t des pieds varus equins. J Genet Hum 11:65-71. Kopits E (1937): Die als Flughaut bezeichneten Missbildungen und deren operative Behandlung. Arch Orthop Unfall Chir 37:538-549. Lannelongue (1879):Cited by Cervenka e t al. (1967). Leck GD, Aird J C (1984): An incomplete form of the popliteal pterygium syndrome? Br J Dent 157:318-319. Lewis E (1948):Congenital webbing of the lower limbs. Proc R SOC Med 41:31. Long J C , Blandford SE (1962): Ankyloblepharon filiforme adnatum with cleft lip and palate. Am J Ophthalmoi 53:126. Marquardt W (1937): Die angeborene Flughautbildung und ihre konservative Behandlung. Z Orthop 66/67:379-386. Mathis H (1962):Uber einen Fall von Ernahrungsschwierigkeitenbei connataler Syngnathie. Dtsch Zahnarztl Z 17:1167-1171. Matolcsy T (1936):Uber die chirurgische Behandlung der angeborenen Flughaut. Arch Klin Chir 185:675-688. McKeown CME, Harris R (1988): An autosomal dominant multiple pterygium syndrome. J Med Genet 25:96-103. Negishi T, Azuma H (1981): Popliteal pterygium syndrome with special reference to its variable abnormalities. Clin Orthop Surg (Jpn) 32:369-374. Neuman Z, Shulman J (1961):Congenital sinuses of the lower lip. Oral Surg 14:1415-1420. Oberst (1910): Cited in Cervenka e t al. (1967). Opitz J M (1988): Pathogenetic analysis of certain developmental and genetic ectodermal defects. In Salinas CF, Optiz JM, Paul NW (eds): “Recent Advances in Ectodermal Dysplasias.” New York: Alan R. Liss, for the National Foundation-March of Dimes, BD:OAS 24(2):75-102. Page RE, Shaw MH (1978):The popliteal web syndrome. Br J Plast Surg 3 1:152- 154. Pashayan H , Lewis MB (1980):A family with the popliteal pterygium syndrome. Cleft Palate J 17:48-51. Pashayan H, Battle CV, Pruzansky S (1974):Popliteal pterygium syndrome. In Bergsma D (ed): “Limb Malformations.” Miami: Symposia Specialists, for the National Foundation-March of Dimes, BD:OAS X(5):252-256. Pfeiffer RA, Tunte W, Reinken M (1970): Das Kniepterygium-Syndrom. Z Kinderheilkd 108:103-116. Preus M, Fraser FC, Fuhrmann W (1974):Cleft palate lateral synechia syndrome without the lateral synechia (CP + / LS syndrome). Teratology 9:135-142. Raithei H, Schweckendiek W, Hillig U (1979): Das KniepterygiumSyndrom i n 3 Generationen. Z Kinderchir 26:56-62. Rapp RS, Hodgkin WE (1968):Anhydrotic ectodermal dysplasia: Autosoma1 dominant inheritance with palate and lip abnormalities. J Med Genet 5:269-272. Rintala A, Lahti A (1970):The facio-genito-popliteal syndrome. Scand J Plast Reconstr Surg 4:67-71. ~

Popliteal Pterygium Syndrome Rosselli D, Gulienetti R (1961):Ectodermal dysplasia. B r J Plast Surg 14:190-204. Rydgier L (1891): Casuistische Mittheilungen. Arch Klin Chir 34:769-771. Schinzel A, Klausler M (1986): The Van der Woude syndrome (dominantly inherited lip pits and clefts). J Med Genet 23:291-294. Schonenberg H (1955): Uber die Kombination von Lippen-KieferGaumen-Spalten mit Extremitatenmissbildungen. Z Kinderheilkd 76:79-90. Schramm G (1940): Uber die angeborene Flughautbildung. 2 Orthop 70:189-195. Shved IA, Lazjuk GI, Ostrovskaya TI, Cherstvoy ED (1983): The popliteal pterygium syndrome (A condition of the main anatomical structures of the lower limbs). Folia Morphol 21:258-265. Speigel J, Colton A (1985):AEC syndrome: Ankyloblepharon, ectoderma1 defects, and cleft lip and palate. J Am Acad Dermatol 12:810-815. Steinberg B, Saunders V (1987): Popliteal pterygium syndrome. Oral Surg 63:17-20.

205

Temtamy S,McKusick VA (1978): “The Genetics of Hand Malformations.” New York: Alan R. Liss, Inc., for the National FoundationMarch of Dimes, BD:OAS XIV(3):301-322. Toriello HV, Lindstrom JA, Waterman DF (1979): Re-evaluation of CHANDS. J Med Genet 16:316-317. Tr6lat U (1869): S u r un vice de conformation tres-rare de la levre inferieure. J Med Chir R a t 40:442-445. Van der Woude A (1954): Fistula labii inferiosis congenita and its association with cleft lip and palate. Am J Hum Genet 6:244-256. Warbrick JG, McIntyre JR, Ferguson GA (1952): Remarks on the etiology of congenital bilateral fistula of the lower lip. Br J Plast Surg 4:254-262. Williams DW (1963):Anomaly ofthe scrotum and testes: Simple plastic repair. J Urol 89:860-863. Wolff J (1889): Ueber einen Fall von angeborener Flughautbildung. Arch Klin Chir 38:66-73. Wynne JM, Fraser AG, Herman R (1982): Massive oral membrane in the popliteal web syndrome. J Pediatr Surg 17:59-60.

N Y

P P

N Y

N N P

P

.__

Hamarnoto & Matsumoto t19841

Gorlm et a1 (19681 Hackenbroch 119241

I N N

N

P

P

Y

S

P

N

Y

P

N

N

Y

N

B

N N

N

P

Fevre & Languepin 119621 Frohlich et al (19771

Y

P

N

N

P

Escobar & Wearer 119781

F

B

N N Y

Y Y N

M P

Y

Y

B

Y

N

N

N

Y

N

P

P

B

P

N N Y

Y

Y

Deskin & Sawyer

N

Y

B P B

B

N

N

P

N

Y N

P

Dahmen (19621

B

B

Y

B

R3-4

L2-3.4-5

N

N

N

B

N

N

N

N

N

N

N

N

N

N

N

R

B

B

N N B

N

N

N

B N N N

N

N N N

N

N

B

N

N N

N

N N N

R'

N El-2

B

B B

S

B B N

N N N

N

N L B N N

N N

N N

B N

N

N

B

N

Y

N

N

N

N

N

N Y Y

Y

N

N

Y N

Y

N Y Y

Y N

Y Y Y

N N N N N

N Y

N

N Y

N

N

2

N -

N

3

N N

N

N

N N B4~5 N N

N

R2~3

4~5

N

toes

B 3

toes

N B 3

N

L 3 5. R 1~2.

B 3-47

B 2~5? B 3~47

B3-4

N

N

92-3. 4~5

N R3-5. L 2-3. 4-5

Y

N N

N

4-5

N B 2 - 3 ,

N

Y

N

N

N

N

N

N

Y

Y

N

N

Y

Y

N

N

N

N

N

Y

N

Y

N

Y

N

Y

N

N N N

N N Y

N

N

Y N N Y

N

N

N

N

Y N

N

N N

N N N

N N

N

N

N

Y N N

Y

N

N

N N

N

N N

N

Y N

N N

N N N

N N

N

N

N

N

N

N R 3 - 5 N

N B 4 - 5 N

N N N

N

N

N

N N

N

Y L 4 - 5 N Y N B 4 toes

N B 2 - 3 N N N N Y N N

Y B

Y

~ _ _ _ . ~ _ _ _ _ _ _ _ _ _

B

B P

N N

Y Y

€1

Champion & Cregan 119591

Bixler e t al (19731

B

N B

Y N

B

N

N N

Y

Y

P P

,19691 Basch t18921 ' (18911

N

,P

P

€::::

N

P

Bajaj & Bailey

Audino et al. (19841

Aberle-Horstenepg (19371

~

Reference

~~

Appendix A. A Review of the Literature

~~

F

F

M

M

F

F

M

M

F F M

F

F

M

F F

F

F M

F F M

F F

F

Y

N

Y

I.

L

N

N

N

N

N

N

N

N

N

Y

Y

N

N

N

N

N

N

Y

Y

Y

N

Y

Y

Y

Y

N

N

N

Y

N

N

Z

N

I

N Y

N

N

N N

N

Y

N

Y N

N

N

N N

Y

Cleft l m Lower TW Skin re la^ Fam>lial Ankylo- Pal IBir hp Syn- Popllteal Hand Hand Varus syndac~ Toe Toenail pyramid Crural crypt^ Scrotum Penis Labial Clitorotionship2 or not blephaion Pal (P! pits gnathia web syndaetyly absence3 feet tyly absence hypoplasm t ~ e web Sex orchidism abnormal abnormal hypoplasla megal) ~~~~

Other

retarded Polydactyl) left 6th toe. hypo plast,e tnternal genitalia

clllta, SCOllOSIS.

Constrrctlo" base first toes. extra phalanx bare 2nd fin^ ger. medial thumb Hands said to look like child Bilat inguinal hernias Small uterus. spina bifida o c ~

Family I slight arm restriction, father bifid "YUlil, aunt ""l lateral fuotpol,dactyl, Mather, mat aunt & her child, had bilat~ era1 4 5 toe s y n ~ dactyly. patient SCOIIObIE & occult spinal dysraphism Muhple cafe a" lait spots

Maternal grand father cleft lip

Upper Cer\lcal spine abnormal, died

~~

observations

N N Y N

Y

N N N N

Y Y Y N

119701

Pfetffer et al

1: N N Y

Y

Y

N

N

Y

Y

Y

N

Y

N

P P

Page & S h a a (19781 Pashayan 119741

Pashayan & Lewis 119801

Y Y

N

P

Marquardt 119371

r;

Y

N

P

Leck & Aird 119841 Lewis 119481

N

N

P

N

Y

Y

Y

Y Y Y Y

P S

N

Y N N L

N

P

Y

L

N

N

N

Y Y Y

N

Y

Y

Y

N

P

P

ce

r

P

Kooits 119371

Klem 119621

Kind 118701

Herold et al 119861 Hirakawa et al (19841 Khan et al (19861-{

(19671

Hecht & Jarvinen

Iransson et a~ (19761

B

B

P B

L

B

P

B

B

P B

B

B

N

B

B

P

P B P N

B

N

P

B B B

B

B

B

Y

Y

Y Y

N

Y

Y

Y

N

N N

N

Y

N

Y

Y

Y

N N N N

N

N

Y

Y Y Y

Y

Y

Y

N

N

N Y

Y

N

Y

N

N

N N

N

Y

N

N

N

Y

Y N N Y

Y

'

Y

N Y Y

N

Y

Y

L

R

N B

L

R

B

R

R

B N

B

N

B

R

N

Y

N N N B

B

L

N

R

B

N

B

B

B

N

N

N

N N

N

N

N

N

N

N N

N

N

N

N

N

N

N N N N

N

N

N

N N N

N

N

Bh

N

N N

N

N

B3-4

N

82.5

N

N

N

N

N

B3-4

B3-4

N

N N N N

N

N

N

N N N

N

N

B3-4

N

N

N N

N

N

N

N

Y

N N

N

N

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Y

N

Y

N N N N

Y

N

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Y

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N N

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N N N

N

7#

absent

Y

Y

N N

N

N

N

Y

N

N

N

N

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N N N N

N

N

N

Toe

4

N

N

N N N

Y

Y

Y

N

N

N N N

R4~5

R 3-4

N

B 2-3. R4~5

B 2-3, 3-4 mild B 2-3. 3~4 mild N

4-5

R 3-4. L2~3~ B2~3 N R 2-3 R 2-3, 4-5 B 2-3,

N

N

N B 4-5 N

B 4-5, L h b sent hifid 1-2 N N

B2-5

N

N

N N

N

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Y

N

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(continued)

incisor

with frenulum

head Absent upper

Sear back of

m"b&

Blocked tearducts7,spma hifida occults, inguinal hernia. minimal nebs left foot Both paients congenital deaf Pyramid on 2nd toe. first COUSl" once removed cleft lip palate Ihp flex$on COntractUreS Palate had no

Retarded growth & development. died 6 years

resia

Rt choanal at-

Small ,a*

Excessoral webs

on hp

Family 1, an^ kyloglossia Family 1 Family 2 Family 2, testes lsmalll Family 2. bifid Sndtoenail. scar

Short stature. metatarsal hypopIas1a & fusions. sibhandsyndactyly, sib, father, paternal grandfather. hrachydactyly and short Family 1. An kyloglossia

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