434:. p63 mutations have been implicated in other human malformation conditions as well, including AEC or Hay–Wells syndrome, limb–mammary syndrome, ADULT syndrome, and non-syndromic split hand–split foot malformation. When comparing the data for these syndromes, each syndrome has a distinct pattern and type of mutations, with extensive genotype–phenotype correlations. Brunner and colleagues found that most of the p63 mutations associated with EEC "involve amino acid substitutions in the DNA binding domain common to all known p63 isoforms". The findings of their study propose that the most frequently mutated arginine codons associated with EEC are 204, 227, 279, 280, and 304, with these five amino acid mutations accounting for 75% of all reported cases of EEC syndrome. Other studies have had similar findings. One study found three of the five listed amino acid mutations in their subjects and noted that when 200 control chromosomes were tested, these three mutant alleles were not present.
414:, each parent contributes 23 chromosomes; 22 autosomal chromosomes and one sex chromosome. As stated above, EEC syndrome is an autosomal dominant disorder. This means that there is an abnormal gene on one of the autosomal (non-sex) chromosomes from either parent. Because the gene is dominant, only one parent must contribute the abnormal gene for the child to inherit the disease and the contributing parent will usually have the disease, due to the expression of the dominant gene in the parent. Some characteristics of autosomal dominant inheritance patterns include a vertical transmission pattern, meaning that the disease phenotype is seen in generation after generation. Also, the recurrence risk is 50% and there are an equal number of affected males and females. Though we can calculate the chance of inheritance of the gene, the degree of expression cannot be calculated.
61:
37:
368:
446:. The frameshift mutation introduces a premature stop codon that affected the α isotope, but does not affect the β and γ isotopes of p63. From this, it can be concluded that mutant p63α isotopes seem to play a major role in the pathogenesis of EEC syndrome. It seems that p63α is the predominant p63 isotope in epithelial basal cell layers, which are the cell type often associated with the anomalies found in patients with EEC syndrome.
455:
be significant interfamilial and intrafamilial variability in expressivity, more noticeably between rather than within families. Because of this variability, it is possible that there is more than one genetic locus involved in the actual manifestation of the syndrome in any given person. Other notably proposed sections of the involved chromosome include 3q27, and more highly disputed areas, including 7q11.2–q21.3
348:
and fold upward, forming the neural folds, which eventually meet to form the neural tube and neural crest. Because these two events occur at roughly the same time in embryological development, abnormalities found in this syndrome can involve not only the ectodermal cells, but also disruption to development in the mesectodermal layer constituted by the neural crest.
478:
identified as a compound targeting and reactivating p53 mutants based on a cell-based screening for rescuing the apoptotic activity of p53, as efficient to rescue R304W mutation defect. Of interest, similar effect had been observed on keratinocytes derived from the same patients. PRIMA-1MET could become an effective therapeutic tool for EEC patients.
482:
very useful in distinguishing between syndromes that present with very similar clinical findings. There is much debate in current literature regarding clinical markers for syndromic diagnoses. Genetic findings could have great implications in clinical diagnosis and treatment of not only EEC, but also many other related syndromes.
454:
EEC can be both familial and sporadic, both cases relating back to abnormalities of the p63 gene. This means that in some cases, EEC expresses de novo in a child of unaffected parents (sporadic) due to spontaneous mutation, in addition to the existing autosomal dominant inherited form. There seems to
463:
P63-deficient mice lack all squamous epithelia and their derivatives, including hair, whiskers, teeth, as well as the mammary, lacrimal, and salivary glands. Particularly striking are severe limb truncations with forelimbs showing a complete absence of the phalanges and carpals, and variable defects
347:
There are two layers of mesoderm; intraembryonic and extraembryonic. As the intraembryonic layer grows laterally, it becomes continuous with the extraembryonic layer, forming the chorion (contributing to the blood supply). At the same time during embryonic development, the ectoderm begins to thicken
248:
may not be as hydrated as is necessary during the adduction phase of vocal fold vibration (due to lack of lubrication), a complete seal may not be accomplished between the folds and mucosal wave movement may be disrupted. This results in air escapement between the folds and the production of breathy
481:
Further genetic research is necessary to identify and rule out other possible loci contributing to EEC syndrome, though it seems certain that disruption of the p63 gene is involved to some extent. In addition, genetic research with an emphasis on genetic syndrome differentiation should prove to be
179:
Ectrodactyly involves the deficiency or absence of one or more central digits of the hand or foot and is also known as split hand–split foot malformation (SHFM). The hands and feet of people with ectrodactyly are often described as "claw-like" and may include only the thumb and one finger (usually
477:
Modeling EEC syndrome in vitro has been achieved by reprogramming EEC fibroblasts carrying mutations R304W and R204W into induced pluripotent stem cell (iPSC) lines. EEC-iPSC recapitulated defective epidermal and corneal fates. This model further identified PRIMA-1MET, a small compound that was
468:
This striking data offers convincing support for the p63 gene hypothesis. This study is also cited in the demonstration that the growth and patterning of the underlying mesenchyme is highly dependent on the apical ectodermal ridge of the limbs, as well as the maxillary and mandibular branchial
426:, within the region of D19S894 and D19S416 has been postulated as the locus for the abnormalities found in EEC syndrome. This is supported by reports (though conflicting) regarding an association of cleft lip +/- palate on locus 19q, which suggests that EEC could be an allelic variant.
351:"What these structures have in common is that their development and morphogenesis depends on the signaling between specialized ectodermal cells and the underlying mesoderm. Epithelial-mesenchymal interactions between the apical ectodermal ridge (AER) and the underlying
458:
A study supports the hypothesis of the p63 gene as the locus for the mutations associated with EEC syndrome. The study is known as the p63 knockout mice study, in which the phenotypes of p63-deficient mice are described. The description of the mice is as follows:
291:
due to ossicular anomalies is often encountered in patients with EEC syndrome, which can have significant impacts on language acquisition. Also, the impaired cognitive functioning that sometimes accompanies EEC can inhibit language acquisition.
469:
ectoderm that are so prominently disturbed in these mice. All of these findings are consistent with the clinical presentation of EEC in humans and may explain the association of limb malformation and clefting that are found in this syndrome.
261:+/- palate and use this marker as a means of distinguishing EEC from other syndromes, such as AEC syndrome (ankyloblepharon, ectodermal dysplasia, and clefting) in which other types of clefting are found. Other authors include
429:
More recently, the p63 gene has been targeted in numerous studies. The p63 gene is a homologue of the tumor suppressor gene p53, though this is not indicative that patients with EEC are more likely to develop
1462:
277:
and velopharyngeal incompetence. Because of this, compensatory articulation strategies including retruded articulation and glottal compensation are often incorporated into the patient's speech.
205:. In addition, abnormalities of ectodermal derivatives, neuroectodermal derivatives, and mesectodermal derivatives are often found. The ectodermal derivative abnormalities can affect the
464:
of ulnae and radiae and hindlimbs that are lacking altogether…The p63 mutations act in a dominant fashion in humans, giving rise to a phenotype that resembles that of p63 knockout mice.
442:
The mutations found in EEC are missense mutations, meaning that there is a single amino acid change in the protein, as opposed to premature termination of protein synthesis, known as a
529:
300:
The ectodermal dysplasia associated with EEC syndrome arises from abnormalities in the embryonic ectoderm, as described above. Very early in embryonic development, the embryonic
1455:
257:
There is much discrepancy in the literature regarding the exact nature of the facial clefting involved in EEC. Some authors claim that the clefting involved in EEC is always
1255:
Shen J, van den
Bogaard EH, Kouwenhoven EN, Bykov VJ, Rinne T, Zhang Q, Tjabringa GS, Gilissen C, van Heeringen SJ, Schalkwijk J, van Bokhoven H, Wiman KG, Zhou H (2013).
217:. Neuroectodermal derivatives that can be affected include sensory placodes, cutaneous pigmental cells, and hair buds. Mesectodermal derivatives affected can include the
1448:
897:
Moerman P, Fryns JP (1996). "Ectodermal dysplasia, Rapp–Hodgkin type in a mother and severe ectrodactyly–ectodermal dysplasia–clefting syndrome (EEC) in her child".
937:
Ruhin B, Martinot V, Lafforgue P, Catteau B, Manouvrier-Hanu S, Ferri J (2001). "Pure ectodermal dysplasia: retrospective study of 16 cases and literature review".
201:
resulting in dry (hypohydrotic), often scale-like skin, sparse and usually coarse scalp hair that is often blonde, sparse eyebrows and eyelashes, and small brittle
1367:
GeneReviews/NCBI/NIH/UW entry on
Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome or AEC Syndrome, Hay-Wells Syndrome. Includes: Rapp-Hodgkin Syndrome
180:
either the little finger, ring finger, or a syndactyly of the two) with similar abnormalities of the feet. It is sometimes referred to as "lobster claw" syndrome.
402:
Current research regarding EEC syndrome is focused on the genetic components contributing to the presented traits found in patients with EEC. A normal human
378:
236:
The hypohydrotic symptoms of ectodermal dysplasia described above are evidenced not only in the skin of affected individuals, but also in their
2267:
422:
Genetics research relating to EEC has made great strides in recent years, but many findings are currently being debated in the literature.
910:
189:. These abnormalities affect both the superficial ectodermal layer, as well as the mesectodermal layer constituted by the neural crest.
1440:
1257:"APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations"
1871:
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881:
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1206:"Impaired epithelial differentiation of induced pluripotent stem cells from EEC patients is rescued by APR-246/PRIMA-1MET"
2020:
1394:
316:. It is from these three types of cells that all body organs originate. In general terms, ectodermal cells generate the
2482:
1579:
629:
608:
714:
Ramirez D, Lammer EJ (2004). "Lacrimoauriculodentodigital syndrome with cleft lip/palate and renal manifestations".
2467:
1670:
980:
Peterson-Falzone SJ, Caldarelli DD, Landahl KL (1981). "Abnormal laryngeal vocal quality in ectodermal dysplasia".
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is further impaired by the numerous dental anomalies, including missing or malformed teeth found in EEC syndrome.
1589:
1557:
2179:
1604:
2441:
2417:
2048:
1088:"Syndromic ectrodactyly with severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19"
2148:
2090:
2076:
1829:
1502:
1034:"Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts"
767:
519:
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only (CPO) in conjunction with ectrodactyly and ectodermal dysplasia as sufficient for a diagnosis of EEC.
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Peterson-Falzone, Sally J.; Mary A. Hardin-Jones; Michael P. Karnell; Betty Jane McWilliams (2001).
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The speech deficits associated with EEC syndrome are numerous. The clefting often causes
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661:"Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome"
185:
Ectodermal dysplasia describes abnormalities of structures derived from the embryonic
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deficits are also associated with EEC syndrome and are attributed to two factors.
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2009:
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328:(as well as the numerous derivatives mentioned above). Mesodermal cells generate
111:
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and one pair of sex chromosomes, constituting a total of 46 chromosomes. During
355:, denoted the progress zone, are required for normal morphogenesis of the limb.
1768:
1518:
1421:
1366:
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voice, which often accompanies the skin abnormalities of ectodermal dysplasia.
202:
2461:
2118:
1740:
551:"Twenty-four cases of the EEC syndrome: clinical presentation and management"
498:
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911:
10.1002/(SICI)1096-8628(19960614)63:3<479::AID-AJMG12>3.0.CO;2-J
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and sweat glands, as well as hairs, dental enamel, nails, lens, and the
1990:
1331:
524:
352:
301:
222:
147:
139:
94:
44:
Ectrodactyly–ectodermal dysplasia–cleft syndrome is autosomal dominant
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727:
403:
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1103:
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186:
108:
979:
530:
List of dental abnormalities associated with cutaneous conditions
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2226:
1851:
1837:
1782:
1762:
1599:
1085:
1032:
Barrow LL, van
Bokhoven H, Daack-Hirsch S, et al. (2002).
431:
333:
226:
218:
159:
151:
1031:
229:, head muscles and conjunctival cells, cervicofacial vascular
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1984:
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1951:
1937:
1923:
1909:
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1804:
1776:
1748:
337:
317:
135:
1316:"A step closer toward therapies for p63-related disorders"
807:
502:
122:. Other features noted in association with EEC include
620:
James, William; Berger, Timothy; Elston, Dirk (2005).
1086:
O'Quinn JR, Hennekam RC, Jorde LB, Bamshad M (1998).
1376:
1261:
Proceedings of the
National Academy of Sciences, USA
1210:
Proceedings of the
National Academy of Sciences, USA
1203:
622:
2376:Ectrodactyly–ectodermal dysplasia–cleft syndrome 3
1166:Speech and Hearing Science: Anatomy and Physiology
1136:
869:
769:
490:These people are noted as having this condition.
2459:
872:Genetics, Syndromes, and Communication Disorders
659:Celli J, Duijf P, Hamel BC, et al. (1999).
548:
197:Ectodermal dysplasia is characterized by absent
22:Ectrodactyly–ectodermal dysplasia–cleft syndrome
951:10.1597/1545-1569_2001_038_0504_pedrso_2.0.co_2
658:
549:Buss PW, Hughes HE, Clarke A (September 1995).
344:, the digestive system and the urinary system.
97:–split foot–ectodermal dysplasia–cleft syndrome
2268:Yemenite deaf-blind hypopigmentation syndrome
1456:
808:Brunner HG, Hamel BC, Van Bokhoven H (2002).
713:
601:Fitzpatrick's Dermatology in General Medicine
304:differentiate into three types of cells: the
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863:
861:
859:
857:
855:
853:
1313:
763:
761:
759:
757:
755:
753:
1463:
1449:
1204:Shalom Feuerstein R.; et al. (2012).
867:
542:
406:includes 22 pairs of autosomal or non-sex
233:, and part of the maxillofacial skeleton.
59:
35:
1339:
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1280:
1231:
1221:
1111:
1081:
1079:
1077:
1057:
1027:
1025:
1023:
1021:
1019:
1017:
1015:
1013:
1011:
973:
850:
833:
810:"The p63 gene in EEC and other syndromes"
803:
801:
799:
797:
795:
793:
709:
707:
679:
576:
1872:Posterior polymorphous corneal dystrophy
1702:Autoimmune polyendocrine syndrome type 1
1177:
1175:
932:
930:
928:
750:
472:
2063:Anterior segment mesenchymal dysgenesis
1134:
1128:
654:
652:
650:
648:
646:
644:
642:
640:
638:
192:
114:. EEC is characterized by the triad of
2460:
1163:
1157:
1074:
1008:
890:
790:
704:
614:
158:, occasional cognitive impairment and
1595:X-linked adrenal hypoplasia congenita
1444:
1172:
925:
449:
1647:Greig cephalopolysyndactyly syndrome
1181:
994:10.1001/archotol.1981.00790410038010
899:American Journal of Medical Genetics
635:
593:
362:
340:, and endodermal cells generate the
2021:Iridogoniodysgenesis, dominant type
13:
2305:
1360:
1092:American Journal of Human Genetics
268:
252:
14:
2504:
1372:
939:Cleft Palate-Craniofacial Journal
716:Cleft Palate-Craniofacial Journal
485:
2035:Lymphedema–distichiasis syndrome
1631:Tricho–rhino–phalangeal syndrome
1605:Familial partial lipodystrophy 3
366:
134:, decreased pigmentation of the
2299:(0) Other transcription factors
1590:Estrogen insensitivity syndrome
1558:Androgen insensitivity syndrome
1307:
1248:
1197:
1182:Hall, Judith G. (August 2007).
174:
169:
2180:Hyperimmunoglobulin E syndrome
1585:PHA1AD pseudohypoaldosteronism
1143:. Baltimore: Paul H. Brookes.
868:Shprintzen, Robert J. (1997).
150:, absent punctae in the lower
1:
2442:Atrichia with papular lesions
681:10.1016/S0092-8674(00)81646-3
535:
358:
295:
2488:Syndromes affecting the skin
2149:Popliteal pterygium syndrome
2091:Enlarged vestibular aqueduct
1930:Waardenburg syndrome 1&3
1715:(3) Helix-turn-helix domains
1474:relating to deficiencies of
520:List of cutaneous conditions
437:
118:, ectodermal dysplasia, and
7:
2478:Syndromes affecting hearing
2249:Premature ovarian failure 7
2105:Premature ovarian failure 3
1977:Congenital hypothyroidism 2
1164:Zemlin, Willard R. (1981).
1038:Journal of Medical Genetics
814:Journal of Medical Genetics
556:Journal of Medical Genetics
508:
417:
397:
10:
2509:
2396:Transcription coregulators
2166:with minor groove contacts
1553:Thyroid hormone resistance
1314:Zhou H, Aberdam D (2013).
1139:Children with Disabilities
982:Archives of Otolaryngology
603:. (6th ed.). McGraw-Hill.
599:Freedberg, et al. (2003).
88:, and also referred to as
2483:Syndromes affecting teeth
2428:
2418:Rubinstein–Taybi syndrome
2403:
2394:
2325:
2298:
2278:
2244:SRY XY gonadal dysgenesis
2214:
2188:
2172:
2163:
2129:
2049:Bamforth–Lazarus syndrome
2001:
1901:
1721:
1714:
1694:
1661:Duane-radial ray syndrome
1639:
1618:
1610:SF1 XY gonadal dysgenesis
1540:
1531:
1511:
1490:
1483:
1380:
1135:Batshaw, Mark L. (2002).
48:
43:
34:
26:
21:
2286:Cleidocranial dysostosis
1503:Saethre–Chotzen syndrome
624:. (10th ed.). Saunders.
244:production. Because the
128:urinary tract infections
107:disorder inherited as a
2468:Syndromes with dysmelia
2263:Waardenburg syndrome 4c
1963:Coloboma of optic nerve
1811:Tooth and nail syndrome
1651:Pallister–Hall syndrome
1282:10.1073/pnas.1201993110
1223:10.1073/pnas.1201753109
1184:"Chromosomes and Genes"
876:. Singular Pub. Group.
289:Conductive hearing loss
164:conductive hearing loss
2206:Ulnar–mammary syndrome
2164:(4) β-Scaffold factors
2144:Van der Woude syndrome
1676:Townes–Brocks syndrome
1549:Intracellular receptor
466:
375:This section is empty.
142:, missing or abnormal
2380:Limb–mammary syndrome
2368:Rapp–Hodgkin syndrome
2340:Pitt–Hopkins syndrome
1916:Papillorenal syndrome
1891:Mowat–Wilson syndrome
1797:Nail–patella syndrome
1681:Acrocallosal syndrome
515:Limb–mammary syndrome
473:In vitro model of EEC
461:
130:, obstruction of the
124:vesicoureteral reflux
2222:Campomelic dysplasia
2201:Li–Fraumeni syndrome
1686:Myotonic dystrophy 2
1656:Denys–Drash syndrome
1476:transcription factor
1050:10.1136/jmg.39.8.559
826:10.1136/jmg.39.6.377
569:10.1136/jmg.32.9.716
193:Ectodermal dysplasia
101:ectodermal dysplasia
76:ectodermal dysplasia
2016:Axenfeld syndrome 3
1830:Axenfeld syndrome 1
1769:SPD1 synpolydactyly
1534:DNA-binding domains
1436:OMIM entries on AEC
1273:2013PNAS..110.2157S
772:Cleft Palate Speech
209:including mammary,
2372:Hay–Wells syndrome
2196:Holt–Oram syndrome
1958:Gillespie syndrome
1877:Fuchs' dystrophy 3
1755:Currarino syndrome
1332:10.4161/rdis.24247
450:Genetic expression
105:autosomal dominant
99:is a rare form of
2455:
2454:
2451:
2450:
2321:
2320:
2294:
2293:
2159:
2158:
1736:Ohtahara syndrome
1710:
1709:
1580:Kennedy's disease
1527:
1526:
1498:Feingold syndrome
1484:(1) Basic domains
1472:Genetic disorders
1431:
1430:
1150:978-1-55766-581-2
883:978-1-56593-620-1
783:978-0-8151-3153-3
444:nonsense mutation
395:
394:
275:hypernasal speech
231:endothelial cells
132:nasolacrimal duct
68:
67:
16:Medical condition
2500:
2401:
2400:
2303:
2302:
2170:
2169:
1741:Lissencephaly X2
1719:
1718:
1626:Barakat syndrome
1538:
1537:
1488:
1487:
1465:
1458:
1451:
1442:
1441:
1378:
1377:
1354:
1353:
1343:
1311:
1305:
1304:
1294:
1284:
1267:(6): 2157–2162.
1252:
1246:
1245:
1235:
1225:
1216:(6): 2152–2156.
1201:
1195:
1194:
1192:
1191:
1179:
1170:
1169:
1168:. Prentice-Hall.
1161:
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765:
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747:
728:10.1597/03-080.1
711:
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683:
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633:
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612:
597:
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546:
390:
387:
377:You can help by
370:
363:
64:
63:
55:Medical genetics
39:
19:
18:
2508:
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2503:
2502:
2501:
2499:
2498:
2497:
2458:
2457:
2456:
2447:
2424:
2390:
2317:
2313:Kabuki syndrome
2290:
2274:
2210:
2184:
2165:
2155:
2125:
1997:
1897:
1706:
1690:
1635:
1614:
1533:
1532:(2) Zinc finger
1523:
1507:
1479:
1478:or coregulators
1469:
1432:
1427:
1426:
1389:
1375:
1363:
1361:Further reading
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162:anomalies, and
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1098:(1): 130–135.
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988:(5): 300–304.
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499:tennis player
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2404:Coactivator:
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1188:. Retrieved
1165:
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412:reproduction
401:
383:
379:adding to it
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283:
279:Articulation
272:
263:cleft palate
256:
235:
215:internal ear
199:sweat glands
196:
184:
178:
175:Ectrodactyly
170:Presentation
126:, recurrent
116:ectrodactyly
93:
90:EEC syndrome
89:
85:
72:Ectrodactyly
70:
69:
30:EEC syndrome
408:chromosomes
322:spinal cord
246:vocal folds
156:photophobia
27:Other names
2462:Categories
1417:DiseasesDB
1326:: e24247.
1190:2008-10-01
536:References
525:Cleft hand
386:March 2017
359:Management
353:mesenchyme
302:stem cells
296:Embryology
223:hypodermis
148:hypoplasia
95:split hand
2326:Ungrouped
967:208150324
776:. Mosby.
438:Mutations
404:karyotype
332:vessels,
259:cleft lip
238:phonation
211:pituitary
207:epidermis
146:, enamel
50:Specialty
1350:25002990
1301:23355676
1242:23355677
1068:12161593
959:11522173
844:12070241
744:20874635
736:15352854
698:18193864
690:10535733
509:See also
418:Genetics
398:Research
314:endoderm
310:mesoderm
306:ectoderm
285:Language
187:ectoderm
82:syndrome
2077:ACD/MPV
1411:C536189
1341:3932939
1292:3568378
1269:Bibcode
1233:3568301
1186:. Merck
1122:9443880
1113:1376811
1059:1735218
1002:7224950
919:8737656
835:1735150
587:8544192
578:1051673
152:eyelids
109:genetic
2412:CREBBP
2232:MODY 5
2227:MODY 3
1991:STHAG3
1944:MODY 9
1852:POU3F4
1844:DFNA15
1838:POU4F3
1783:MODY 4
1763:HOXD13
1671:MRX 89
1666:MODY 7
1600:MODY 1
1400:129900
1348:
1338:
1299:
1289:
1240:
1230:
1147:
1120:
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780:
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688:
628:
607:
585:
575:
432:tumors
334:muscle
324:, and
312:, and
227:dentin
219:dermis
160:kidney
57:
2354:TNDM1
2348:ZFP57
2257:SOX10
2113:FOXP3
2099:FOXL2
2085:FOXI1
2071:FOXF1
2057:FOXE3
2043:FOXE1
2029:FOXC2
2010:FOXC1
1858:DFNX2
1824:PITX2
1791:LMX1B
1422:34402
963:S2CID
740:S2CID
694:S2CID
664:(PDF)
342:lungs
330:blood
326:teeth
242:voice
203:nails
144:teeth
112:trait
103:, an
84:, or
80:cleft
2384:OFC8
2362:TP63
2334:TCF4
2279:4.11
2138:IRF6
2119:IPEX
1985:PAX9
1971:PAX8
1952:PAX6
1938:PAX4
1924:PAX3
1910:PAX2
1885:ZEB2
1866:ZEB1
1816:OFC5
1805:MSX1
1777:PDX1
1749:MNX1
1573:CAIS
1568:MAIS
1563:PAIS
1406:MeSH
1395:OMIM
1346:PMID
1297:PMID
1238:PMID
1145:ISBN
1118:PMID
1064:PMID
998:PMID
955:PMID
915:PMID
878:ISBN
840:PMID
778:ISBN
732:PMID
686:PMID
668:Cell
626:ISBN
605:ISBN
583:PMID
338:bone
336:and
318:skin
240:and
140:skin
138:and
136:hair
92:and
2306:0.6
2238:SF1
2215:4.7
2189:4.3
2173:4.2
2130:3.5
2002:3.3
1902:3.2
1730:ARX
1722:3.1
1695:2.5
1640:2.3
1619:2.2
1551:):
1541:2.1
1512:1.3
1491:1.2
1336:PMC
1328:doi
1287:PMC
1277:doi
1265:110
1228:PMC
1218:doi
1214:110
1108:PMC
1100:doi
1054:PMC
1046:doi
990:doi
986:107
947:doi
907:doi
830:PMC
822:doi
724:doi
676:doi
573:PMC
565:doi
381:.
86:EEC
2464::
2437:HR
1420::
1409::
1398::
1344:.
1334:.
1322:.
1318:.
1295:.
1285:.
1275:.
1263:.
1259:.
1236:.
1226:.
1212:.
1208:.
1174:^
1116:.
1106:.
1096:62
1094:.
1090:.
1076:^
1062:.
1052:.
1042:39
1040:.
1036:.
1010:^
996:.
984:.
961:.
953:.
943:38
941:.
927:^
913:.
903:63
901:.
852:^
838:.
828:.
818:39
816:.
812:.
792:^
752:^
738:.
730:.
720:41
718:.
706:^
692:.
684:.
672:99
670:.
666:.
637:^
581:.
571:.
561:32
559:.
553:.
503:UK
501:,
497:-
320:,
308:,
225:,
221:,
166:.
154:,
2444:)
2440:(
2382:/
2378:/
2374:/
2370:/
1649:/
1547:(
1464:e
1457:t
1450:v
1387:D
1352:.
1330::
1324:1
1303:.
1279::
1271::
1244:.
1220::
1193:.
1153:.
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