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Ectrodactyly with fibular aplasia: A separate entity?
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European Journal of Medical Genetics 51 (2008) 488e496 http://www.elsevier.com/locate/ejmg
Signs in dysmorphology
Ectrodactyly with fibular aplasia: A separate entity? Leonie A. Menke a,1, Emilia K. Bijlsma b, Anthonie J. van Essen c, Marie-Jose´ H. van den Boogaard d, Rick R. van Rijn e, Jan Maarten Cobben a,* a
Department of Paediatric Genetics, Emma Children’s Hospital/Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands b Department of Clinical Genetics, Leiden University Medical Centre, The Netherlands c Department of Genetics, University Medical Centre Groningen, The Netherlands d Department of Medical Genetics, University Medical Centre Utrecht, The Netherlands e Department of Radiology, Academic Medical Centre, Amsterdam, The Netherlands Received 5 February 2008; accepted 22 April 2008 Available online 2 May 2008
Abstract E/FA is the combination of ectrodactyly (split hand/foot malformation, SHFM) and fibular aplasia. It is a rare disorder considered to be inherited in an autosomal dominant fashion with reduced penetrance and variable expression. In order to determine recurrence risks for the two patients we describe, the literature on inheritance of E/FA was carefully reviewed. In our opinion, only two of the eight families previously reported as examples of familial E/FA may fit this judgment. Until mutation analysis of all SHFM genes is possible, the question remains whether these familial cases represent autosomal dominant E/FA, or an allelic variant of an SHFM subtype. Many sporadic patients with presumed E/FA may represent the fibular developmental field defect, which is a non-genetic entity with a low recurrence risk. We therefore suggest that the high recurrence risk associated with autosomal dominant inheritance should not be counselled in patients with E/FA unless their family shows the following characteristics: (1) at least one patient shows typical SHFM combined with fibular aplasia, (2) multiple limbs are affected, and (3) multiple family members are affected in at least two generations. Ó 2008 Elsevier Masson SAS. All rights reserved. Keywords: Fibula; Ulna; Split hand/foot malformation; Ectrodactyly; Limb deficiency
* Corresponding author. Tel.: þ31 20 5667508; fax: þ31 20 6917735. E-mail address: [email protected] (J.M. Cobben). 1 Present address. Leiden University Medical Center, The Netherlands. 1769-7212/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2008.04.001
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1. Introduction Ectrodactyly, a somewhat imprecise term for split hand/foot malformation (SHFM), is a congenital limb malformation that involves the central rays of the hand or foot (OMIM 183600). Typical SHFM is often familial. It usually affects more than one limb and is characterised by a deep median cleft. However, monodactyly, syndactyly and aplasia or hypoplasia of the phalanges, metacarpals and metatarsals may also occur. Conversely, atypical SHFM presents as a more transversal defect. It usually occurs unilaterally, and is generally considered to be non-genetic [1,5]. Fibular aplasia and/or hypoplasia is the most common malformation of the long bones and occurs as part of several chromosomal, X-linked, autosomal dominant or autosomal recessive syndromes. It may also occur sporadically as part of the fibular developmental field defect or the femurefibulaeulna (FFU) complex [15]. The fibular developmental field defect includes defects in the pubic portion of the pelvis, proximal femur, patella, fibula and lateral and/or central foot rays [15]. The FFU complex includes patients with defects of the fibula and/or postaxial foot rays [12,13]. Both are regarded as non-genetic entities with low recurrence risks [14,15]. In 2002, a review article was published on the concurrence of SHFM and fibular aplasia (E/FA) [6]. In this review, patients were considered as having E/FA if fibular aplasia or hypoplasia concurred with a central limb ray deficiency. However, family members with other limb defects were also included. By this means, the authors listed 23 sporadic cases and 8 families. They concluded that there was good evidence for the existence of an autosomal dominant predisposing gene and suggested that most sporadic cases were the result of incomplete penetrance.
Fig. 1. Photograph of patient 1 showing short lower legs, dislocated ankles and split feet (arrow).
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Recently, two Dutch patients showed the combination of E/FA. In order to determine recurrence risks, we carefully reviewed the literature on the mode of inheritance. 2. Clinical reports 2.1. Patient 1 After an uneventful pregnancy of 41 þ 1 weeks, a boy (patient 1) was born by spontaneous vaginal delivery. His birth weight was 3350 g (0.5 SD) and Apgar scores were 7 and 7 at 1 and 5 min, respectively. Because of respiratory insufficiency, he was intubated for one day and received antibiotics for one week. He was the first child of healthy, unrelated parents. The family history revealed no congenital anomalies. The mother had used malaria prophylaxis from 6 until 4 weeks before conception. She had not used any teratogens associated with limb defects during the pregnancy and did not have diabetes. Bilateral anomalies of his lower legs and feet were immediately noticed after birth (Fig. 1). He had short lower legs, dislocated ankles and split feet. The upper limbs were normal and no other dysmorphic features were seen. Radiographs of the legs showed hypoplastic femora, fibular aplasia and short, bowed tibiae (Fig. 2). In the right foot only a broad first, and one other, unidentifiable ray were present (Fig. 3A). In the left foot, the second and third rays seemed to be missing (Fig. 3B), since a large distance separated the first, and what appeared to be the fourth and the fifth rays. Syndactyly was present in the latter two rays. The karyotype and a subtelomeric screen were normal and DNA analysis of the TP63 gene did not reveal a mutation. Ultrasonography of the cerebrum, heart and abdomen was normal. Both feet and parts of the tibiae were amputated, after which the boy was able to walk with prostheses. His mental development has been normal.
Fig. 2. Radiograph of the lower extremities of patient 1, showing bilateral fibular aplasia and anterior bowing of the left tibia (arrow).
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Fig. 3. Radiographs of both feet of patient 1. (A) The right foot shows a broad, biphalangeal first ray, and one other, unidentifiable ray. (B) The left foot has a large distance between the first biphalangeal ray and the presumed fourth and fifth rays (arrow).
2.2. Patient 2 Patient 2, a boy, was the third child of healthy, unrelated parents. The pregnancy had been complicated with the HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) and intrauterine growth retardation. A Caesarean section was performed at a gestational age of 35 þ 5 weeks. His birth weight was 1845 g (1.9 SD) and his length 43 cm (1.7 SD). Apgar scores were 8 and 8 at 1 and 5 min, respectively. The mother did not have diabetes and had not used teratogens during the pregnancy. His younger brother had TowneseBrocks syndrome (an autosomal dominant malformation syndrome characterised by renal, anal, ear, and thumb anomalies) with somatic mosaicism of a mutation in the SALL1 gene. Besides that, no limb defects or congenital anomalies were present in the family. His right leg was short and the right foot had three toes. The medial toe seemed to represent the hallux; the second toe was hypoplastic. The left leg and upper extremities were normal. Radiographs of the right lower leg and foot showed a three-toed foot with a hypoplastic second ray (Fig. 4A), and fibular aplasia with a short, bowed tibia (Fig. 4B). Ultrasonography showed normal abdominal organs. 3. Discussion We present two patients with the combination of SHFM and fibular aplasia. Patient 1 had bilateral hypoplastic femurs, bilateral fibular aplasia and a somewhat symmetrical reduction defect in both feet. Patient 2 showed fibular aplasia and a quite typical central reduction defect in one limb. To determine recurrence risks in patients with missing rays of the hands or feet, it is important to classify the abnormalities as a central or lateral reduction defect. In a patient with fibular aplasia, a lateral defect favours the FFU complex, and a central defect favours E/FA. However,
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Fig. 4. Radiographs of the right foot and ankle of patient 2. (A) A three-toed foot with a hypoplastic second ray. Note the gap between the first and second rays (arrow). (B) Lateral radiograph showing fibular aplasia and anterior bowing of the tibia (arrow).
it is often difficult to identify the origin of the missing rays. In patient 1, both feet were affected and a large cleft separated the presumed first and lateral metatarsals of the left foot. Although unilaterally affected, patient 2 also showed a quite typical central reduction defect. Therefore, the diagnosis E/FA seemed more appropriate than FFU for both our patients.
Fig. 5. Families reported as examples of dominant inheritance of fibular aplasia with ectrodactyly. The graphical representation of these pedigrees is derived from the cited publications, with omission of the unaffected, non-interposing family members. Square ¼ male; circle ¼ female; filled left side, black ¼ typical split hand foot malformation; filled left side, grey ¼ other hand or foot defect rather than a typical split hand foot malformation; filled right side, black ¼ fibular aplasia; filled right side, grey ¼ ulnar aplasia; question mark ¼ limb disorder not clear. (A) Patient III:1 had bilateral asymmetric hypoplastic fibulae with lateral defects in both feet, and a hypoplastic second metatarsal and first proximal phalanx in the left foot; patient I: 1 had a leg length discrepancy of 1.6 cm, presumed to be caused by proximal femoral focal deficiency [2]. (B) Patient II:1 showed the typical femurefibulaeulna complex with absence of the right fourth and fifth fingers, bilateral fibular aplasia and absence of the right fifth toe. His mother had an atypical split hand [3]. (C) Both siblings were described as having the femurefibulaeulna (FFU) complex. Patient II:1 had bilateral fibular aplasia with postaxial foot defects; patient II:2 had ulnar aplasia, humeroradial synostosis and two missing lateral fingers on the left arm [14]. (D) Patient II:1 had fibular aplasia right, and a central ray deficiency of the right foot; patient II:2 had a complex hand malformation with hypoplastic second and fourth rays, and syndactyly, which might be classified as central ray dysplasia of the hand (not a typical split hand/foot malformation) [10]. (E) Patient IV:1 had atypical split hand left, brachydactyly of the right hand, bilateral fibular aplasia, and complex foot malformations with absence of three toes on the right foot and absence of two toes on the left foot, it is hard to determine whether the toe deficiencies were lateral or central; patient IV-2 had brachydactyly of the central fingers in the left hand (without involvement of the metacarpals), and absence and fusion of several phalanges in the right foot [8]. (F) Patient V:1 had split hand right, bilateral fibular aplasia and split feet; patient III:3 was said ‘‘to have been affected like the proband’’ [16]. (G) Three family members showed typical split hand/foot malformations (patients II:2, III:1 and IV:1), and six family members had unilateral or bilateral fibular aplasia (patients II:2, II:3, III:3, III:4, IV:1 and IV:2) [4]. (H) Six family members showed typical split hand/foot malformations (patients III:1, III:3, III:4, IV:1, IV:2 and IV:3). Furthermore, patient IV:1 had bilateral fibular aplasia, and patient IV:3 had bilateral ulnar aplasia [9].
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Estimating recurrence risks for the parents of these patients seemed difficult to assess from literature data. In a review article on inheritance of E/FA, the risk for offspring of affected and unaffected parents was estimated on the basis of published families [6]. The segregation ratio or offspring penetrance for unaffected parents was calculated to be 0.21. However, no estimations were made for isolated cases and no corrections were made for ascertainment bias and publication bias. Moreover, family members of a patient with E/FA were also included if they had limb defects other than SHFM or fibular aplasia. When looking at the eight original reports of the families that were presented as examples of familial E/FA, we think that at least six of them (Fig. 5AeF) may not support autosomal dominant inheritance with reduced penetrance. In the following, we will illustrate this by briefly discussing these families. The report of Bohring and Oppermann concerned a patient with bilateral fibular hypoplasia, bilateral oligodactyly and a unilateral split foot (Fig. 5A) [2]. His grandfather had a leg length difference of 1.6 cm because of a shorter left femoral shaft and a slightly smaller left collodiaphyseal angle. Although the authors considered that the leg length difference in the grandfather could be a normal variant, they hypothesized that the findings in the family were different expressions of a familial form of proximal femoral focal deficiency (PFFD). Although the first criterion for hemihypertrophy of the legs (a leg length discrepancy of more than 1 cm) was met, the other criterion (a visible difference in circumference between the two legs) was not [7]. In our opinion, this leg length difference could be physiologic. Moreover, PFFD is regarded as a non-genetic entity. The occurrence of the leg length difference in a family member of a child with E/FA could be coincidental. The report of Czeizel et al. concerned a mother with a unilateral hand malformation, and her son who had multiple limb defects (Fig. 5B) [3]. The mother had a U-shaped defect of the left hand with absence of the second, third, and fourth fingers. The corresponding metacarpals showed distal hypoplasia, and the first and fifth fingers were hypoplastic. We agree with Czeizel et al. that this hand malformation should be classified as a classical case of atypical split hand. Her son (case 53/1975) showed the typical FFU complex: his fourth and fifth fingers of the right hand were absent and he had bilateral fibular aplasia with absence of the right fifth toe. Therefore, we think that the family reported by Czeizel et al. does not qualify as an example of familial E/FA. In the family reported by Lenz et al., the defects seemed to be lateral rather than central (Fig. 5C) [14]. We therefore think that this family should be classified as having the FFU complex rather than E/FA. We think that the monozygotic twins reported by Halal should not be considered as familial cases. Because monozygotic twins share the same genetic content, they represent a sporadic case from a genetic point of view (Fig. 5D) [10]. In the family of Genuardi et al., the limb defects of the second cousin of the index patient consisted of the absence and fusion of several phalanges in both feet and hands [8]. We think this resembles the presentation of the amniotic band sequence, which is a non-genetic entity [11]. Based on the distance between the patients in the family, as well as the absence of clinical resemblance between them, we suggest that the concurrence of the limb defects in the family is coincidental (Fig. 5E). In the family of Temtamy and McKusick, four phenotypically normal family members interposed two patients, of whom the latter was ‘‘said to have been affected like the proband’’ [16]. In our view, a family of two distantly related patients of whom one was not proved to have the same limb anomalies, cannot strongly support autosomal dominant inheritance (Fig. 5F). In contrast to these families, we think that two other families have more convincingly showed familial E/FA. Deragna et al. [4] described seven affected family members in three
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generations (Fig. 5G). Two family members showed the combination of fibular aplasia and typical SHFM in multiple limbs. Four family members showed fibular aplasia without SHFM, of whom three had bilateral fibular aplasia. One patient had SHFM without fibular aplasia. Graham and Badgley [9] reported on an SHFM-family in which six family members from two generations were affected by typical central reduction defects (Fig. 5H). One family member had bilateral fibular aplasia combined with a unilateral split hand defect. Another family member showed bilateral ulnar deficiency and bilateral split hands. It should however be noted that just one family member had fibular aplasia. Thus, as far as we are aware, only two reports of possible familial E/FA have been published. These two families showed the following characteristics: (1) a typical SHFM combined with fibular aplasia present in at least one patient, (2) multiple limbs affected, and (3) multiple family members affected in at least two generations. However, the impression arises that the families of Deragna et al. [4] and Graham and Badgley [9] may have had typical autosomal dominant SHFM with the occasional expression of ulnar aplasia and fibular aplasia (present in one and four family members, respectively). Until mutation analysis of all SHFM genes is possible, the question remains whether familial E/FA is an extremely rare separate entity, or the representation of an allelic variant of an SHFM subtype. We told the parents of patients 1 and 2 that the defects in their children probably were representations of E/FA. We furthermore told them that we considered recurrence risks for following pregnancies to be low, but that these risks might be higher for offspring of the affected child. Prenatal sonography was offered for subsequent pregnancies. We conclude that the existence of a separate entity familial E/FA is uncertain. Before counselling a high recurrence risk in a case of E/FA, we propose that a family has to meet the following criteria: (1) at least one patient shows fibular aplasia together with a typical SHFM, (2) multiple limbs of at least one patient are affected, and (3) multiple family members in at least two generations are affected. If these criteria are not met, we suggest that in a large number of patients, the anomalies may belong to the fibular developmental field defect. Competing interests/funding None.
Acknowledgements The parents of the children described in this report are acknowledged for their helpful cooperation. We thank Dr. Jane Evans for providing the pages on which the family of Czeizel et al. was described. We thank Hester Heidinga for her secretarial assistance.
References [1] A.J. Barsky, Cleft hand: classification, incidence, and treatment. Review of the literature and report of nineteen cases, J. Bone Joint Surg. Am. 46 (1964) 1707e1720. [2] A. Bohring, H.C. Oppermann, A further case of vertical transmission of proximal femoral focal deficiency? Am. J. Med. Genet. 71 (1997) 194e196. [3] A. Czeizel, J.A. Evans, I. Kodaj, W. Lenz, Congenital Limb Deficiencies in Hungary: Genetic and Teratologic Epidemiological Studies, Akade´mia Kiado´, Budapest, 1994.
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[4] S. Deragna, V. Zucco, E. Ferrante, Hereditary transmission of aplasia of the fibula, and of ectrodactyly. Study of a family, Quad. Clin. Ostet. Ginecol. 21 (1966) 1295e1308. [5] A.M. Elliott, M.H. Reed, A.E. Chudley, B.N. Chodirker, J.A. Evans, Clinical and epidemiological findings in patients with central ray deficiency: split hand foot malformation (SHFM) in Manitoba, Canada, Am. J. Med. Genet. A 140 (2006) 1428e1439. [6] J.A. Evans, M.H. Reed, C.R. Greenberg, Fibular aplasia with ectrodactyly, Am. J. Med. Genet. 113 (2002) 52e58. [7] H.V. Firth, J.A. Hurst, Oxford Desk Reference Clinical Genetics, Oxford University Press, Oxford, 2005. [8] M. Genuardi, M. Zollino, A. Bellussi, W. Fuhrmann, G. Neri, Brachy/ectrodactyly and absence or hypoplasia of the fibula: an autosomal dominant condition with low penetrance and variable expressivity, Clin. Genet. 38 (1990) 321e326. [9] J.B. Graham, C.E. Badgley, Split-hand with unusual complications, Am. J. Hum. Genet. 7 (1955) 44e50. [10] F. Halal, Monozygotic twins discordant for fibular aplasia, Am. J. Med. Genet. 41 (1991) 434e437. [11] Y. Kino, Clinical and experimental studies of the congenital constriction band syndrome, with an emphasis on its etiology, J. Bone Joint Surg. Am. 57 (1975) 636e643. [12] D. Kuhne, W. Lenz, D. Petersen, H. Schonenberg, Defects of the femur and fibula with amelia, peromelia or ulnar defects of the arm. A syndrome, Humangenetik 3 (1967) 244e263. [13] W. Lenz, U. Feldmann, Unilateral and asymmetric limb defects in man: delineation of the femurefibulaeulna complex, Birth Defects Orig. Artic Ser. 13 (1977) 269e285. [14] W. Lenz, M. Zygulska, J. Horst, FFU complex: an analysis of 491 cases, Hum. Genet. 91 (1993) 347e356. [15] S.O. Lewin, J.M. Opitz, Fibular a/hypoplasia: review and documentation of the fibular developmental field, Am. J. Med. Genet.(Suppl. 2) (1986) 215e238. [16] S.A. Temtamy, V.A. McKusick, The genetics of hand malformations, Birth Defects Orig. Artic Ser. 14 (1978) 57e58.
MODEL
Available online at www.sciencedirect.com
European Journal of Medical Genetics 51 (2008) 488e496 http://www.elsevier.com/locate/ejmg
Signs in dysmorphology
Ectrodactyly with fibular aplasia: A separate entity? Leonie A. Menke a,1, Emilia K. Bijlsma b, Anthonie J. van Essen c, Marie-Jose´ H. van den Boogaard d, Rick R. van Rijn e, Jan Maarten Cobben a,* a
Department of Paediatric Genetics, Emma Children’s Hospital/Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands b Department of Clinical Genetics, Leiden University Medical Centre, The Netherlands c Department of Genetics, University Medical Centre Groningen, The Netherlands d Department of Medical Genetics, University Medical Centre Utrecht, The Netherlands e Department of Radiology, Academic Medical Centre, Amsterdam, The Netherlands Received 5 February 2008; accepted 22 April 2008 Available online 2 May 2008
Abstract E/FA is the combination of ectrodactyly (split hand/foot malformation, SHFM) and fibular aplasia. It is a rare disorder considered to be inherited in an autosomal dominant fashion with reduced penetrance and variable expression. In order to determine recurrence risks for the two patients we describe, the literature on inheritance of E/FA was carefully reviewed. In our opinion, only two of the eight families previously reported as examples of familial E/FA may fit this judgment. Until mutation analysis of all SHFM genes is possible, the question remains whether these familial cases represent autosomal dominant E/FA, or an allelic variant of an SHFM subtype. Many sporadic patients with presumed E/FA may represent the fibular developmental field defect, which is a non-genetic entity with a low recurrence risk. We therefore suggest that the high recurrence risk associated with autosomal dominant inheritance should not be counselled in patients with E/FA unless their family shows the following characteristics: (1) at least one patient shows typical SHFM combined with fibular aplasia, (2) multiple limbs are affected, and (3) multiple family members are affected in at least two generations. Ó 2008 Elsevier Masson SAS. All rights reserved. Keywords: Fibula; Ulna; Split hand/foot malformation; Ectrodactyly; Limb deficiency
* Corresponding author. Tel.: þ31 20 5667508; fax: þ31 20 6917735. E-mail address: [email protected] (J.M. Cobben). 1 Present address. Leiden University Medical Center, The Netherlands. 1769-7212/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2008.04.001
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1. Introduction Ectrodactyly, a somewhat imprecise term for split hand/foot malformation (SHFM), is a congenital limb malformation that involves the central rays of the hand or foot (OMIM 183600). Typical SHFM is often familial. It usually affects more than one limb and is characterised by a deep median cleft. However, monodactyly, syndactyly and aplasia or hypoplasia of the phalanges, metacarpals and metatarsals may also occur. Conversely, atypical SHFM presents as a more transversal defect. It usually occurs unilaterally, and is generally considered to be non-genetic [1,5]. Fibular aplasia and/or hypoplasia is the most common malformation of the long bones and occurs as part of several chromosomal, X-linked, autosomal dominant or autosomal recessive syndromes. It may also occur sporadically as part of the fibular developmental field defect or the femurefibulaeulna (FFU) complex [15]. The fibular developmental field defect includes defects in the pubic portion of the pelvis, proximal femur, patella, fibula and lateral and/or central foot rays [15]. The FFU complex includes patients with defects of the fibula and/or postaxial foot rays [12,13]. Both are regarded as non-genetic entities with low recurrence risks [14,15]. In 2002, a review article was published on the concurrence of SHFM and fibular aplasia (E/FA) [6]. In this review, patients were considered as having E/FA if fibular aplasia or hypoplasia concurred with a central limb ray deficiency. However, family members with other limb defects were also included. By this means, the authors listed 23 sporadic cases and 8 families. They concluded that there was good evidence for the existence of an autosomal dominant predisposing gene and suggested that most sporadic cases were the result of incomplete penetrance.
Fig. 1. Photograph of patient 1 showing short lower legs, dislocated ankles and split feet (arrow).
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Recently, two Dutch patients showed the combination of E/FA. In order to determine recurrence risks, we carefully reviewed the literature on the mode of inheritance. 2. Clinical reports 2.1. Patient 1 After an uneventful pregnancy of 41 þ 1 weeks, a boy (patient 1) was born by spontaneous vaginal delivery. His birth weight was 3350 g (0.5 SD) and Apgar scores were 7 and 7 at 1 and 5 min, respectively. Because of respiratory insufficiency, he was intubated for one day and received antibiotics for one week. He was the first child of healthy, unrelated parents. The family history revealed no congenital anomalies. The mother had used malaria prophylaxis from 6 until 4 weeks before conception. She had not used any teratogens associated with limb defects during the pregnancy and did not have diabetes. Bilateral anomalies of his lower legs and feet were immediately noticed after birth (Fig. 1). He had short lower legs, dislocated ankles and split feet. The upper limbs were normal and no other dysmorphic features were seen. Radiographs of the legs showed hypoplastic femora, fibular aplasia and short, bowed tibiae (Fig. 2). In the right foot only a broad first, and one other, unidentifiable ray were present (Fig. 3A). In the left foot, the second and third rays seemed to be missing (Fig. 3B), since a large distance separated the first, and what appeared to be the fourth and the fifth rays. Syndactyly was present in the latter two rays. The karyotype and a subtelomeric screen were normal and DNA analysis of the TP63 gene did not reveal a mutation. Ultrasonography of the cerebrum, heart and abdomen was normal. Both feet and parts of the tibiae were amputated, after which the boy was able to walk with prostheses. His mental development has been normal.
Fig. 2. Radiograph of the lower extremities of patient 1, showing bilateral fibular aplasia and anterior bowing of the left tibia (arrow).
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Fig. 3. Radiographs of both feet of patient 1. (A) The right foot shows a broad, biphalangeal first ray, and one other, unidentifiable ray. (B) The left foot has a large distance between the first biphalangeal ray and the presumed fourth and fifth rays (arrow).
2.2. Patient 2 Patient 2, a boy, was the third child of healthy, unrelated parents. The pregnancy had been complicated with the HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) and intrauterine growth retardation. A Caesarean section was performed at a gestational age of 35 þ 5 weeks. His birth weight was 1845 g (1.9 SD) and his length 43 cm (1.7 SD). Apgar scores were 8 and 8 at 1 and 5 min, respectively. The mother did not have diabetes and had not used teratogens during the pregnancy. His younger brother had TowneseBrocks syndrome (an autosomal dominant malformation syndrome characterised by renal, anal, ear, and thumb anomalies) with somatic mosaicism of a mutation in the SALL1 gene. Besides that, no limb defects or congenital anomalies were present in the family. His right leg was short and the right foot had three toes. The medial toe seemed to represent the hallux; the second toe was hypoplastic. The left leg and upper extremities were normal. Radiographs of the right lower leg and foot showed a three-toed foot with a hypoplastic second ray (Fig. 4A), and fibular aplasia with a short, bowed tibia (Fig. 4B). Ultrasonography showed normal abdominal organs. 3. Discussion We present two patients with the combination of SHFM and fibular aplasia. Patient 1 had bilateral hypoplastic femurs, bilateral fibular aplasia and a somewhat symmetrical reduction defect in both feet. Patient 2 showed fibular aplasia and a quite typical central reduction defect in one limb. To determine recurrence risks in patients with missing rays of the hands or feet, it is important to classify the abnormalities as a central or lateral reduction defect. In a patient with fibular aplasia, a lateral defect favours the FFU complex, and a central defect favours E/FA. However,
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Fig. 4. Radiographs of the right foot and ankle of patient 2. (A) A three-toed foot with a hypoplastic second ray. Note the gap between the first and second rays (arrow). (B) Lateral radiograph showing fibular aplasia and anterior bowing of the tibia (arrow).
it is often difficult to identify the origin of the missing rays. In patient 1, both feet were affected and a large cleft separated the presumed first and lateral metatarsals of the left foot. Although unilaterally affected, patient 2 also showed a quite typical central reduction defect. Therefore, the diagnosis E/FA seemed more appropriate than FFU for both our patients.
Fig. 5. Families reported as examples of dominant inheritance of fibular aplasia with ectrodactyly. The graphical representation of these pedigrees is derived from the cited publications, with omission of the unaffected, non-interposing family members. Square ¼ male; circle ¼ female; filled left side, black ¼ typical split hand foot malformation; filled left side, grey ¼ other hand or foot defect rather than a typical split hand foot malformation; filled right side, black ¼ fibular aplasia; filled right side, grey ¼ ulnar aplasia; question mark ¼ limb disorder not clear. (A) Patient III:1 had bilateral asymmetric hypoplastic fibulae with lateral defects in both feet, and a hypoplastic second metatarsal and first proximal phalanx in the left foot; patient I: 1 had a leg length discrepancy of 1.6 cm, presumed to be caused by proximal femoral focal deficiency [2]. (B) Patient II:1 showed the typical femurefibulaeulna complex with absence of the right fourth and fifth fingers, bilateral fibular aplasia and absence of the right fifth toe. His mother had an atypical split hand [3]. (C) Both siblings were described as having the femurefibulaeulna (FFU) complex. Patient II:1 had bilateral fibular aplasia with postaxial foot defects; patient II:2 had ulnar aplasia, humeroradial synostosis and two missing lateral fingers on the left arm [14]. (D) Patient II:1 had fibular aplasia right, and a central ray deficiency of the right foot; patient II:2 had a complex hand malformation with hypoplastic second and fourth rays, and syndactyly, which might be classified as central ray dysplasia of the hand (not a typical split hand/foot malformation) [10]. (E) Patient IV:1 had atypical split hand left, brachydactyly of the right hand, bilateral fibular aplasia, and complex foot malformations with absence of three toes on the right foot and absence of two toes on the left foot, it is hard to determine whether the toe deficiencies were lateral or central; patient IV-2 had brachydactyly of the central fingers in the left hand (without involvement of the metacarpals), and absence and fusion of several phalanges in the right foot [8]. (F) Patient V:1 had split hand right, bilateral fibular aplasia and split feet; patient III:3 was said ‘‘to have been affected like the proband’’ [16]. (G) Three family members showed typical split hand/foot malformations (patients II:2, III:1 and IV:1), and six family members had unilateral or bilateral fibular aplasia (patients II:2, II:3, III:3, III:4, IV:1 and IV:2) [4]. (H) Six family members showed typical split hand/foot malformations (patients III:1, III:3, III:4, IV:1, IV:2 and IV:3). Furthermore, patient IV:1 had bilateral fibular aplasia, and patient IV:3 had bilateral ulnar aplasia [9].
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Estimating recurrence risks for the parents of these patients seemed difficult to assess from literature data. In a review article on inheritance of E/FA, the risk for offspring of affected and unaffected parents was estimated on the basis of published families [6]. The segregation ratio or offspring penetrance for unaffected parents was calculated to be 0.21. However, no estimations were made for isolated cases and no corrections were made for ascertainment bias and publication bias. Moreover, family members of a patient with E/FA were also included if they had limb defects other than SHFM or fibular aplasia. When looking at the eight original reports of the families that were presented as examples of familial E/FA, we think that at least six of them (Fig. 5AeF) may not support autosomal dominant inheritance with reduced penetrance. In the following, we will illustrate this by briefly discussing these families. The report of Bohring and Oppermann concerned a patient with bilateral fibular hypoplasia, bilateral oligodactyly and a unilateral split foot (Fig. 5A) [2]. His grandfather had a leg length difference of 1.6 cm because of a shorter left femoral shaft and a slightly smaller left collodiaphyseal angle. Although the authors considered that the leg length difference in the grandfather could be a normal variant, they hypothesized that the findings in the family were different expressions of a familial form of proximal femoral focal deficiency (PFFD). Although the first criterion for hemihypertrophy of the legs (a leg length discrepancy of more than 1 cm) was met, the other criterion (a visible difference in circumference between the two legs) was not [7]. In our opinion, this leg length difference could be physiologic. Moreover, PFFD is regarded as a non-genetic entity. The occurrence of the leg length difference in a family member of a child with E/FA could be coincidental. The report of Czeizel et al. concerned a mother with a unilateral hand malformation, and her son who had multiple limb defects (Fig. 5B) [3]. The mother had a U-shaped defect of the left hand with absence of the second, third, and fourth fingers. The corresponding metacarpals showed distal hypoplasia, and the first and fifth fingers were hypoplastic. We agree with Czeizel et al. that this hand malformation should be classified as a classical case of atypical split hand. Her son (case 53/1975) showed the typical FFU complex: his fourth and fifth fingers of the right hand were absent and he had bilateral fibular aplasia with absence of the right fifth toe. Therefore, we think that the family reported by Czeizel et al. does not qualify as an example of familial E/FA. In the family reported by Lenz et al., the defects seemed to be lateral rather than central (Fig. 5C) [14]. We therefore think that this family should be classified as having the FFU complex rather than E/FA. We think that the monozygotic twins reported by Halal should not be considered as familial cases. Because monozygotic twins share the same genetic content, they represent a sporadic case from a genetic point of view (Fig. 5D) [10]. In the family of Genuardi et al., the limb defects of the second cousin of the index patient consisted of the absence and fusion of several phalanges in both feet and hands [8]. We think this resembles the presentation of the amniotic band sequence, which is a non-genetic entity [11]. Based on the distance between the patients in the family, as well as the absence of clinical resemblance between them, we suggest that the concurrence of the limb defects in the family is coincidental (Fig. 5E). In the family of Temtamy and McKusick, four phenotypically normal family members interposed two patients, of whom the latter was ‘‘said to have been affected like the proband’’ [16]. In our view, a family of two distantly related patients of whom one was not proved to have the same limb anomalies, cannot strongly support autosomal dominant inheritance (Fig. 5F). In contrast to these families, we think that two other families have more convincingly showed familial E/FA. Deragna et al. [4] described seven affected family members in three
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generations (Fig. 5G). Two family members showed the combination of fibular aplasia and typical SHFM in multiple limbs. Four family members showed fibular aplasia without SHFM, of whom three had bilateral fibular aplasia. One patient had SHFM without fibular aplasia. Graham and Badgley [9] reported on an SHFM-family in which six family members from two generations were affected by typical central reduction defects (Fig. 5H). One family member had bilateral fibular aplasia combined with a unilateral split hand defect. Another family member showed bilateral ulnar deficiency and bilateral split hands. It should however be noted that just one family member had fibular aplasia. Thus, as far as we are aware, only two reports of possible familial E/FA have been published. These two families showed the following characteristics: (1) a typical SHFM combined with fibular aplasia present in at least one patient, (2) multiple limbs affected, and (3) multiple family members affected in at least two generations. However, the impression arises that the families of Deragna et al. [4] and Graham and Badgley [9] may have had typical autosomal dominant SHFM with the occasional expression of ulnar aplasia and fibular aplasia (present in one and four family members, respectively). Until mutation analysis of all SHFM genes is possible, the question remains whether familial E/FA is an extremely rare separate entity, or the representation of an allelic variant of an SHFM subtype. We told the parents of patients 1 and 2 that the defects in their children probably were representations of E/FA. We furthermore told them that we considered recurrence risks for following pregnancies to be low, but that these risks might be higher for offspring of the affected child. Prenatal sonography was offered for subsequent pregnancies. We conclude that the existence of a separate entity familial E/FA is uncertain. Before counselling a high recurrence risk in a case of E/FA, we propose that a family has to meet the following criteria: (1) at least one patient shows fibular aplasia together with a typical SHFM, (2) multiple limbs of at least one patient are affected, and (3) multiple family members in at least two generations are affected. If these criteria are not met, we suggest that in a large number of patients, the anomalies may belong to the fibular developmental field defect. Competing interests/funding None.
Acknowledgements The parents of the children described in this report are acknowledged for their helpful cooperation. We thank Dr. Jane Evans for providing the pages on which the family of Czeizel et al. was described. We thank Hester Heidinga for her secretarial assistance.
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