Download Ectrodactyly-Ectodermal Dysplasia

Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome
EEC syndrome is an ectodermal dysplasia syndrome associated with ectrodactyly and cleft lip/palate.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Familial cases (50%)
i. Autosomal dominant inheritance
ii. Variable clinical expression and incomplete
penetrance (93–98%)
b. Sporadic cases (50%): more severe phenotype than
the familial cases
2. At least three distinctive EEC loci identified
a. EEC1 (7q11.2-q21.3)
b. EEC2 (chromosome 19 pericentromeric region)
c. EEC3 (3q27)
3. Molecular basis of EEC3
a. Causative mutations for EEC syndrome have only been
identified in p63 with identification of heterozygous
mutations in the DNA-binding domain of the p63
gene at 3q27
b. The p63 protein
i. A member of the p53 family
ii. Implicated in apoptosis rather than tumor suppression. Increased susceptibility for cancer
development has not been shown in patients with
EEC syndrome
4. A genotype–phenotype correlation described for p63
mutations in EEC syndrome, limb-mammary syndrome,
and isolated split hand/split foot malformation: a specific
pattern of missense mutations exists in EEC syndrome
that are not generally found in split hand/foot malformation or limb-mammary syndrome
5. EEC syndrome as a model of apoptosis disturbance
a. Split hands and feet are caused by a failure of cell
death between fingers and between toes
b. Urogenital anomalies are due to abnormal regression
of Wolffian or Mullerian duct
c. Facial clefts are attributed to the abnormal elimination
of excess cells during fusion of the archetypal plate
4. Ectodermal dysplasia (77%): may exhibit the following
signs:
a. Sparse scalp hair
b. Sparse eyebrows and eyelashes
c. Thin and brittle nails
d. Hypohidrosis
e. Thin and dry skin with an increased susceptibility to
eczema
f. Dental anomalies
i. Hypodontia
ii. Coniform-shaped teeth
iii. Enamel dysplasia
5. Characteristic face
a. Bilateral cleft lip and/or palate (68%)
b. Maxillary hypoplasia
c. Short philtrum
d. Broad nasal tip
e. Choanal atresia
f. Anomalies of the lacrimal ducts resulting in blepharitis,
keratitis, and dacryocystitis (59%)
6. Urogenital defects (23%)
a. Hydronephrosis
b. Hydroureter
c. Renal agenesis
7. Conductive hearing loss (14%)
8. Developmental delay
9. Occasional CNS malformations
a. Rare growth hormone deficiency secondary to hypothalamic-pituitary insufficiency
b. Holoprosencephaly associated with hypogonatdotropic
hypogonadism and central diabetes insipidus
c. Isolated absent septum pellucidum
10. Phenotype overlapping with split hand/foot malformations
DIAGNOSTIC INVESTIGATIONS
1.
2.
3.
4.
5.
Ophthalmologic evaluation for tear duct obstruction
Early audiological assessment
Renal ultrasound for associate renal anomalies
Radiographic evaluation for ectrodactyly
Starch-iodine test (the skin is painted with tincture of
iodine, air dried, and sprayed with starch) after sweat
stimulation with intradermal injections of pilocarpine to
demonstrate hypohidrosis
6. Direct molecular analysis is possible for EEC3
7. Linkage analysis for known EEC2 families
CLINICAL FEATURES
1. Significant intra/interfamilial variability
2. Cardinal signs (triad)
a. Ectrodactyly
b. Ectodermal dysplasia
c. Orofacial clefts
3. Distal limb malformations: highly variable
a. Ectrodactyly (84%)
i. Also called split hand/foot malformation
ii. A central reduction of the hands and feet that is
often associated with syndactyly
b. Present in all four or any combination of extremities
involved or not present at all
GENETIC COUNSELING
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1. Counseling according to autosomal dominant inheritance
a. Patient’s sib:
i. Recurrence risk of 50% if a parent is affected
ii. Recurrence risk not increased if both parents are
normal
b. Patient’s offspring: recurrence risk of 50%
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EEC SYNDROME
c. Dilemmas in counseling due to highly variable clinical
expression
d. Consider the possibility of nonpenetrance due to
gonadal mosaicism
2. Prenatal diagnosis
a. Prenatal ultrasonography
i. Cleft lip/palate
ii. Ectrodactyly
iii. Associated anomalies
b. Molecular genetic analysis of p63 gene mutation
i. On fetal DNA extracted from CVS and amniocytes
by direct sequencing and restriction endonucleases
digestion (loss of AciI site on mutant allele)
ii. Using a preimplantation genetic diagnostic
approach
3. Management
a. Supportive (multi-disciplinary team approach)
i. Artificial tear for tear duct blockage
ii. Anticipate recurrent ophthalmologic infections
iii. Periodic odontologic management to prevent
dental malocclusion and caries
iv. Simple emollients for dry skin
b. Surgery
i. Early surgery for tear duct blockage
ii. Surgery for all defects causing functional
impairment
a) Cleft lip/palate
b) Ectrodactyly
c) Associated anomalies
REFERENCES
Akahoshi K, Sakazume S, Kosaki K, et al.: EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma. Am
J Med Genet 120A:370–373, 2003.
Annerén G, Andersson T, Lindgren PG, et al.: Ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC): the clinical variation and prenatal diagnosis. Clin Genet 40:257–262, 1991.
Barrow LL, van Bokhoven H, Daack-Hirsch S, et al.: Analysis of the p63 gene
in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. J Med Genet 39:559–566, 2002.
Bigatà X, Bielsa I, Artigas M, et al.: The ectrodactyly-ectodermal dysplasiaclefting syndrome (EEC): report of five cases. Pediatr Dermatol 20:113–118,
2003.
Bixler D, Spivack J, Bennett J, et al.: The ectrodactyly-ectodermal dysplasiaclefting (EEC) syndrome. Report of 2 cases and review of the literature.
Clin Genet 3:43–51, 1972.
Bronshtein M, Gershoni-Baruch R: Prenatal transvaginal diagnosis of the ectrodactyly, ectodermal dysplasia, cleft palate (EEC) syndrome. Prenat Diagn
13:519–522, 1993.
Buss FW, Hughes HE, Clarke A: Twenty-four cases of the EEC syndrome: clinical presentation and management. J Med Genet 32:716–723, 1995.
Celli J, Duijf P, Hamel BC, et al.: Heterozygous germline mutations in the
p53 homolog p63 are the cause of EEC syndrome. Cell 99:143–153,
1999.
Crackower MA, Scherer SW, Rommens JM, et al.: Characterization of the split
hand/split foot malformation locus SHFM1 at 7q21.3-q22.1 and analysis
of a candidate gene for its expression during limb development. Hum Mol
Genet 5:571–579, 1996.
Kosaki R, Ohashi H, Yoshihashi H, et al.: A de novo mutation (R279C) in the
P63 gene in a patient with EEC syndrome. Clin Genet 60:314–315, 2001.
Nardi AC, Ferreira U, Netto Junior NR: Urinary tract involvement in EEC syndrome: a clinically study in 25 Brazilian patients. Am J Med Genet
44:803–806, 1992.
O’Quinn JR, Hennekam RC, Jorde LB, et al.: Syndromic ectrodactyly with
severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19. Am J Med Genet 62:130–135, 1992.
Qumsiyeh MB: EEC syndrome (ectrodactyly, ectodermal dysplasia and left
lip/palate) is on 7p11.2-q21.3. Clin Genet 42:101, 1992.
Penchaszadeh VB, de Negrotti TC: Ectrodactyly-ectodermal dysplasia-clefting
(EEC) syndrome: dominant inheritance and variable expression. J Med
Genet 13:281–284, 1976.
Rodini ES, Richieri-Costa A: EEC syndrome: report on 20 new patients, clinical and genetic considerations. Am J Med Genet 37:42–53, 1990.
Roelfsema NM, Cobben JM: The EEC syndrome: A literature study. Clin
Dysmorphol 5:115–127, 1996.
Rollnick BR, Hoo JJ: Genitourinary anomalies are a component manifestation
in the ectodermal dysplasia, ectrodactyly, cleft lip/palate (EEC) syndrome. Am J Med Genet 29:131–135, 1998.
Rodini ES, Richieri-Costa A: EEC syndrome: report on 20 new patients, clinical and genetic considerations. Am J Med Genet 37:42–53, 1990.
Roelfsema NM, Cobben JM: The EEC syndrome: a literature study. Clin
Dysmorphol 5:115–127, 1996.
Scherer SW, Poorkaj P, Massa H, et al.: Physical mapping of the split hand/split
foot locus on chromosome 7 and implication in Syndromic ectrodactyly.
Hum Mol Genet 3:1345–1354, 1994.
South AP, Ashton GH, Willoughby C, et al.: EEC (Ectrodactyly, Ectodermal
dysplasia, Clefting) syndrome: heterozygous mutation in the p63 gene
(R279H) and DNA-based prenatal diagnosis. Br J Dermatol 146:216–220,
2002.
Tse K, Temple IK, Baraitser M: Dilemmas in counseling: The EC syndrome. J
Med Genet 27:752–755, 1990.
Van Bolhoven H, Jung M, Smits AP, et al.: Limb mammary syndrome: a new
genetic disorder with mammary hypoplasia, ectrodactyly, and other
hand/foot anomalies maps to human chromosome 3q27. Am J Hum
Genet 64:538–546, 1999.
Van Bokhoven H, Hamel BCJ, Bamshad M, et al.: p63 gene mutations in EEC
syndrome, Limb-Mammary syndrome, and isolated split hand-split foot
malformation suggest a genotype–phenotype correlation. Am J Hum
Genet 69:481–492, 2001.
Van Maldergem L, Gillerot Y, Vamos E, et al.: Vasopressin and gonadotropin
deficiency in a boy with the ectrodactyly-ectodermal dysplasia-clefting
syndrome. Acta Paediatr 81:365–367, 1992.
Wessagowit V, Mellerio JE, Pembroke AC, et al.: Heterozygous germline missense mutation in the p63 gene underlying EEC syndrome. Clin Exp
Dermatol 25:441–443, 2000.
EEC SYNDROME
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Fig. 1. A stillborn with severe EEC syndrome.
Fig. 3. An infant with EEC syndrome.
Fig. 2. An infant with EEC syndrome.