American Journal of Medical Genetics 104:209213 (2001)
Bilateral Tibial Agenesis With Ectrodactyly(OMIM 119100): Further Evidence for AutosomalRecessive Inheritance
I. Witters,1 K. Devriendt,2 Ph. Moerman,3 J. Caudron,4 C. Van Hole,5 and J.-P. Fryns2*1Department of Obstetrics and Gynecology, University of Leuven, Leuven, Belgium2Center for Human Genetics, University of Leuven, Leuven, Belgium3Department of Pathology, University of Leuven, Leuven, Belgium4Department of Obstetrics and Gynecology, Dendermonde, Belgium5Department of Neonatology, University of Leuven, Leuven, Belgium
We present further evidence for autosomalrecessive inheritance of the bilateral tibialagenesis/ectrodactyly dysostosis. A consan-guineous Turkish couple gave birth to threechildren with malformations. The first, aboy, died neonatally of pulmonary hyper-tension with congenital alveolar capillarydysplasia and also had tibial agenesis andectrodactyly. A second child, a girl, diedafter birth with the same abnormality of thelungs without skeletal malformations. Afterthe birth of three unaffected children, echo-graphic examination at 15 weeks of gesta-tion in the sixth pregnancy documentedagenesis of tibiae and symmetrical ectro-dactyly of hands and feet. Autopsy did notshow additional malformations, and lungdevelopment was normal for gestationalage. This observation also confirms theautosomal recessive inheritance pattern ofcongenital alveolar capillary dysplasia. 2001 Wiley-Liss, Inc.
KEY WORDS: tibial agenesis; ectrodactyly;congenital alveolar capil-lary dysplasia; autosomalrecessive inheritance
Bilateral tibial agenesis combined with ectrodactylyis a rare malformation with variable manifestations ofsplit hand/split foot and tibial hypoagenesis [DerKaloustian and Mnaymneh, 1973; Majewski et al.,
1985; Buyse, 1990]. Familial occurrence has beendocumented, but its mode of inheritance is not clear,and previous reports suggest the possibility of auto-somal dominant [Majewski et al., 1985, 1996; Zlotogora,1994] and recessive [Kohn et al., 1989] forms.
Congenital alveolar capillary dysplasia (CACD) ormisalignment of lung vessels is a complex vascularabnormality of the lungs resulting in pulmonaryhypertension and neonatal death [Vassal et al., 1998].Most reported cases were sporadic, but familial occur-rence with affected sibs was described in at least fourreports [Shohet et al., 1984; Simonton and Chrenka,1993; Boggs et al., 1994; Vassal et al., 1998].
*Correspondence to: J. P. Fryns, Center for Human Genetics,Herestraat 49, B-3000 Leuven, Belgium.E-mail: firstname.lastname@example.org
Received 12 October 2000; Accepted 6 August 2001
DOI 10.1002/ajmg.10056 Fig. 1. Postmortem radiograph of first child.
2001 Wiley-Liss, Inc.
A 31-year-old Turkish woman was referred forultrasonography at 15 weeks of gestation after theprevious birth of two children with malformations. Sheand her husband were first cousins. Their first child, aboy, died neonatally from intractable pulmonaryhypertension with congenital alveolar capillary dyspla-sia. He also had absent tibiae (Fig. 1) and ectrodactylyof hands and feet. The second child, a girl, also diedimmediately after birth with the same complex vascu-lar abnormality of the lungs; however, she lackedskeletal malformations. The three subsequent preg-nancies resulted in the birth of three unaffectedchildren.
Echographic examination at 15 weeks of gestation inthe sixth pregnancy documented absence of tibiae(Fig. 2A) with ectrodactyly of hands (Fig. 2B) and inlaterally and posteriorly rotated clubfeet with split footmalformation and absence of rays 24.
Amniocentesis for karyotype was normal (46,XX)after R-banding and alpha-fetoprotein (AFP) level wasnormal. The parents decided to terminate the preg-nancy, and after induction at 16 weeks of gestation, a
female fetus was expelled (weight 80 g, head circum-ference 11.7 cm).
Clinical examination and postmortem radiographsconfirmed the echographic findings (Figs. 35).Autopsy showed no evidence of additional malforma-tions, with normal-appearing lungs for gestational age.
Here, we describe three affected sibs born to aconsanguineous, healthy Turkish couple: a first childpresented CACD and absent tibiae with ectrodactyly, asecond child had CACD, and a third had absent tibiaeand ectrodactyly without CACD.
CACD or misalignment of pulmonary vessels is a raremalformation with distinct histological findings: (1)failure of formation and ingrowth of alveolar capil-laries, (2) muscular thickening of small pulmonaryarterioles with (3) extension of muscularization to thesmallest intraacinar arterioles, (4) thickened alveolarwalls, (5) anomalously situated pulmonary veins run-ning alongside pulmonary arterioles, (6) reducednumber of alveoli and (7), in some cases, dilatedlymphatic vessels [Janney et al., 1981; Vassal et al.,
Fig. 2. Echographic diagnosis of bilateral tibial agenesis (A) and ectrodactyly of the hands (B) at 15 weeks.
210 Witters et al.
1998]. Most reported cases were sporadic, but affectedsibs were described in at least four reports and supportautosomal recessive inheritance [Shohet et al., 1984;Simonton and Chrenka, 1993; Boggs et al., 1994; Vassalet al., 1998]. A number of associated malformationshave been described: gastrointestinal anomalies (smallbowel volvulus, duodenal stenosis, aganglionosis of thecolon, intestinal malrotation, Meckel diverticulum)[Haworth and Reid, 1976; Khorsand et al., 1985] andgenitourinary malformations (bicornate uterus, hydro-nephrosis, ureteropelvic junction obstruction, cryp-torchidism) [McDonald-McGinn et al., 1992; Boggset al., 1994]. Simonton and Chrenka  reportedCACD in two sibs: the affected brother had brachialamelia and distal phocomelia of the lower limbs, andthe affected sister had phocomelia of the lower limbs.The association of CACD with bilateral tibial agenesisand symmetrical ectrodactyly has not been reported upto now.
The concurrence of bilateral tibial agenesis andectrodactyly is a rare malformation complex withvariable manifestations of split hand/split foot andtibial hypo-agenesis [Der Kaloustian and Mnaymneh,
1973; Majewski et al., 1985]. The ectrodactyly can besevere, as present in the two affected sibs of this report,but may also manifest as syndactyly IIIIV.
The preaxial tibial deficiency may be limited toisolated hypoplasia of the halluces, but more severelimb deficiencies such as peromelia and transversehemimelia have been reported [McKay et al., 1984;Richieri-Costa et al., 1987b; Buyse, 1990]. Associatedskeletal anomalies can be postaxial and interstitialpolydactyly, hypo- or aplasia of ulnae, aplasia ofpatellae and distal hypoplasia, bifurcated femora[Aalami-Harandi and Zahir, 1976; Kapur et al., 1982;Van den Bout and Dommisse, 1983; Majewski et al.,1985].
Femoral bifurcation has also been described in theGollop-Wolfgang complex, which also includes tibialagenesis and hand (foot) ectrodactyly [Gollop et al.,1980; Wolfgang, 1984; Lurie and Ilyina, 1986; Richieri-Costa et al., 1987a; Raas-Rothschild et al., 1999]. Itseems that the tibial agenesis/ectrodactyly syndromeand the Gollop-Wolfgang complex are variable mani-festations of the same tibial developmental field defect[Raas-Rothschild et al., 1999].
Fig. 3. The malformed fetus.
Fig. 4. The malformed hand.
Tibial Agenesis/Ectrodactyly 211
Familial occurrence has been reported [Der Kalous-tian and Mnaymneh, 1973; Mahloudji and Farpour,1974; Mufti and Wood, 1987; Richieri-Costa, 1987;Sener et al., 1989; Wolfgang, 1984; Sener et al., 1990]but the mode of inheritance is not clear.
Kohn et al.  described the occurrence of tibialagenesis with bifurcation of the femora and ectrodac-tyly in sibs born to healthy consanguineous parents,suggesting autosomal recessive inheritance. Additionalsingle cases with consanguineous parents werereported [Der Kaloustian and Mnaymneh, 1973; Mah-loudji and Farpour, 1974; McKay et al., 1984; Wolfgang,1984; Mufti and Wood, 1987; Richieri-Costa, 1987;Sener et al., 1989, 1990].
Majewski et al. [1985, 1996] reviewed the findings in17 reported families with 39 affected sibs and normalparents and also single cases with consanguineousparents and could not exclude heterogeneity with bothautosomal recessive and autosomal dominant forms.These authors preferred autosomal dominant inheri-tance with reduced penetrance [Majewski et al., 1996].
The findings in the present family with two affectedsibs with absent tibiaesplit hand/split foot anomalyborn to consanguineous parents favors autosomalrecessive inheritance.
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Fig. 5. Postmortem roentgenogram of the presented sib.
212 Witters et al.
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INTRODUCTIONCLINICAL REPORTFig. 1Fig. 2Fig. 3Fig. 4Fig. 5