ß 2006 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 140A:2223 – 2226 (2006)
Clinical Report
Elejalde Syndrome—A Case Report ˇilha´nova´,1 Pavlı´na Plevova´,1,2* Romuald C ˇ urˇ´ık,3 Ivo Kaspercˇ´ık,3 and Anna Krˇepelova´4 Eva S 2
1 Department of Medical Genetics, Faculty Hospital, Ostrava, Czech Republic Institute of Pathology & Laboratory of Molecular Pathology, Medical Faculty, Palacky´ University, Olomouc, Czech Republic 3 Department of Pathology, Faculty Hospital, Ostrava, Czech Republic 4 Institute of Genetics, 2nd Medical Faculty of Charles University, Prague, Czech Republic
Received 11 April 2006; Accepted 29 June 2006
Elejalde syndrome (McKusick 200995), also known as acrocephalopolydactylous dysplasia, is a rare condition. We describe a sixth patient with this syndrome which is characterized by craniosynostosis and hyperproliferation of fibroblasts in many tissues including skin, liver, kidney, and pancreas. The cause of the syndrome is the homozygous state of an autosomal recessive mutation. We
present a hypothesis that Elejalde syndrome might be associated with an inactivating FGFR gene mutation. ß 2006 Wiley-Liss, Inc.
Key words: Elejalde syndrome; craniosynostosis-congenital; receptor; fibroblast growth factor; gene
ˇilha´nova´ E, Plevova´ P, C ˇ urˇ´ık R, Kaspercˇ´ık I, Krˇepelova´ A. 2006. How to cite this article: S Elejalde syndrome—A case report. Am J Med Genet Part A 140A:2223–2226.
INTRODUCTION
Elejalde syndrome (McKusick 200995) is a rare autosomal recessive condition comprising high birth weight, swollen globular body with thick skin, apparently short limbs, craniosynostosis with acrocephaly, a short neck with redundant skin folds, postaxial polydactyly, omphalocele, abnormal face, abdominal organomegaly, ascites, cystic renal dysplasia with excessive amount of connective tissue, and perivascular proliferation of nerve fibres found in many organs [Thornton and Stewart, 1997]. The syndrome is also known as acrocephalopolydactylous dysplasia [Elejalde et al., 1977]. We describe a new patient with this syndrome. CLINICAL REPORT
In the 17th week of pregnancy of a 22-year-old mother, ultrasound abnormalities of the fetus were found including abnormal shape of head, short long bones, and hygroma colli. There was no abnormality in AFP and hCG screening. Amniocentesis was performed and a normal karyotype was found (46,XX). Ultrasound abnormalities progressed. The parents decided for a delivery of the fetus. The infant was born in the 36th week of pregnancy by cesarian with a weight of 4,700 g/49 cm with following abnormalities: swollen acrocephalic head, small and abnormally modeled ears, small and flat nose, big
mouth, hypertelorism and epicanthic folds, short thick neck with formation of a soft tissue mass over the posterior scalp and the nape of the neck, protuberant abdomen and short limbs with brachydactyly, and genua recurvata (Figs. 1 and 2a). A clinical diagnosis of Elejalde syndrome was made. The infant died 11 hr after birth of respiratory insufficiency. At autopsy we found synostosis of most cranial sutures (Fig. 2c). Lungs were hypoplastic. The abdominal protruberance was due in part to ascites and in part to organomegaly, the liver being enlarged (weight 235 g), the kidneys were small (weight 9 g) with abnormal cortical lobulation, the pancreas was fibrotic (Table I, Fig. 2b,d). The intestines appeared normal. There was no evidence of cyst formation within the kidneys and the bladder appeared normally formed.
Eva Sˇilha´nova´ and Pavlı´na Plevova´ participated equally on the manuscript preparation. Grant sponsor: Ministry of Education, Youth and Physical Training of the Czech Republic; Grant number: MSM 6198959216. *Correspondence to: Pavlı´na Plevova´, Department of Medical Genetics, Faculty Hospital, Tr. 17. listopadu 1790, 708 52 Ostrava, Czech Republic. E-mail:
[email protected] DOI 10.1002/ajmg.a.31419
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FIG. 1. The appearance of the newborn infant with Elejalde syndrome (a), (b) detail. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
Histological abnormalities were noted in several organs (Fig. 3). Within the liver, there was an expansion of portal tracts by fibrous tissue which extended to connect adjacent portal tracts (Fig. 3a). Well-formed bile ductules were absent from most portal tracts whilst the ductal plates were irregular
and spiky (Fig. 3b). The kidneys did not show capsular fibrosis or the changes of cystic dysplasia but they did appear to have glomerular crowding with a reduction in the numbers of intervening tubules. Some of the glomeruli accumulated eosinophilic material and were sclerotic (Fig. 3c). The
FIG. 2. a: Radiograph of the infant showing relatively short long bones, small chest, hepatomegaly, (b–d) autopsy findings: (b) hepatosplenomegaly (c) premature closure of cranial sutures with deformation of skull, (d) abnormal cortical lobulation of kidneys. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a ELEJALDE SYNDROME TABLE I. Autopsy Findings Weight (g) Birth weight Right lung Left lung Liver Spleen Pancreas Ascites
4,700 14 11 235 23 9 80 ml
Expected weight (g) 2,378 40 37.9 105 7.6 2.8
pancreas showed a mild degree of interstitial fibrosis (Fig. 3d) and nerve trunks appeared somewhat prominent within the fibrous tissue (Fig. 3e). Skin from the abdominal wall showed markedly thickened subcutis composed of abundant loose collagenous tissue containing numerous small blood vessels (Fig. 3f). Fibroblast culture has not been performed. The parents were healthy and non-consanguineous. There were no remarkable abnormalities in their pedigrees. DISCUSSION
So far, only five cases of the syndrome have been described. Elejalde et al. [1977] described two siblings born to consanguineous parents; Lurie et al. [1991] described another case; Nevin et al. [1994] described a 18-week fetus and Thornton and Stewart [1997] a 24-week neonate with the syndrome. The last one had no evidence of craniosynostosis or polydactyly. There was no omphalocele in our patient as in the cases described by Lurie et al. [1991] and Nevin et al. [1994]. It is probable, that
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omphalocele is an occasionally associated condition that results from the high intraabdominal pressure induced by hepatomegaly and ascites. Elejalde et al. [1977] demonstrated an increased rate of fibroblast proliferation in cell culture and it has been suggested that the condition is in fact an overgrowth syndrome. However, the gene responsible for the syndrome has not been identified yet. Most craniosynostosis syndromes involve mutations in the fibroblast growth factor receptor (FGFR) system [reviewed in Aleck, 2004; Ornitz, 2005]. Many human skeletal dysplasias, that commonly involve craniosynostosis, have been attributed to mutations in fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR 3. The craniosynostosis syndromes involving FGFR2 gene include Apert syndrome, Beare-Stevenson cutis gyrata, Crouzon syndrome, Pfeiffer syndrome, Jackson–Weiss syndrome, and a non-syndromic craniosynostosis. Rare mutations in FGFR1 have been described in Pfeiffer syndrome and osteoglophonic dysplasia also characterized by craniosynostosis. Mutations of FGFR3 gene are associated with Muenke and crouzonodermoskeletal syndromes. There are also syndromes associated with mutations in other genes, such as Saethre-Chotzen syndrome due to mutations in the TWIST gene and Boston-type craniosynostosis due to mutations in the MSX2 gene [reviewed in Aleck, 2004; Ornitz, 2005]. FGFRs are receptors for circulating fibroblast growth factors (FGFs). Twenty-two FGFs are known regulators of cell proliferation, differentiation, and migration [Mohammadi et al., 2005]. Each FGF stimulates one of seven cell-membrane associated FGFRs. There is no specificity between the stimulating FGF and the stimulated FGFR. Consequently, any FGF can stimulate any FGFR [Aleck, 2004;
FIG. 3. Histological findings, for details see the text. a: Liver (hematoxylin-eosin, 400), (b) liver (cytokeratin staining, 400; (1) nearly normal bile ductule; (2) irregular ductule), (c) kidney (hematoxylin-eosin, 400; (1) normal glomerulus; (2) glomerulus with accumulation of eosinophilic material; (3) sclerosed glomerulus), (d) pancreas (trichrom staining, 400), (e) pancreas (anti-S100 staining, 400), (f) skin (hematoxylin-eosin, 100).
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Mohammadi et al., 2005]. Remarkably, the FGFRs are responsible for restraining growth. Mutations that enhance the activity of these receptors can cause decreased growth, as seen in achondroplasia. Mutations that decrease the activity of these receptors would be less likely to restrain growth and are said to be ‘‘hypermorphic.’’ Early fusion of a cranial suture is a hypermorphic event [Aleck, 2004]. With respect to these facts, we suggest that Elejalde syndrome might also be associated with an inactivating FGFR gene mutation. Craniosynostosis as a hypermorphic condition is in accord with the findings of hyperproliferation of fibroblasts in many tissues including skin, liver, kidney and pancreas and the reported increased rate of fibroblast proliferation in culture. Unfortunately, we do not have a blood sample from the patient to verify our hypothesis. Elejalde syndrome is thought to be an autosomal recessive trait [Thornton and Stewart, 1997]. Elejalde et al. [1977] reported the occurrence of the syndrome in siblings conceived in a consanguinous marriage. The other above-mentioned craniosynostosis syndromes are caused by autosomal dominant mutations and frequently arise sporadically.
ACKNOWLEDGMENTS
This work was supported by the research project MSM 6198959216. We are obliged to Prof. Zdeneˇk Kola´ˇr for his support and to Ondrˇej Bla´ha for technical help. REFERENCES Aleck K. 2004. Craniosynostosis syndromes in the genomic era. Semin Pediatr Neurol 11:256–261. Elejalde BR, Giraldo C, Jimenez R, Gilbert EF. 1977. Acrocephalopolydactylous dysplasia. Birth Defects Orig Artic Ser 13:53– 67. Lurie IW, Lazjuk GI, Korotkova IA, Cherstvoy ED. 1991. The cerebro-reno-digital syndrome: A new community. Clin Genet 39:104–113. Mohammadi M, Olsen SK, Ibrahimi OA. 2005. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137. Nevin NC, Herron B, Armstrong MJ. 1994. An 18 week fetus with Elejalde syndrome (acrocephalopolydactylous dysplasia). Clin Dysmorphol 3:180–184. Ornitz DM. 2005. FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev 16:205–213. Thornton CM, Stewart F. 1997. Elejalde syndrome: A case report. Am J Med Genet 69:406–408.
