Click here to load reader
Upload
harold
View
225
Download
3
Embed Size (px)
Citation preview
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 (Akahoshi et al. 2003; Barrow et al.
2002; Clements et al. 2010)
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 EEC
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.
c. Pathogenic mutations in the TP63 transcription
factor have been identified as the molecular
basis of EEC syndrome and to date 34 mutations
have been reported (Clements et al. 2010). The
majority of mutations involve heterozygous
missense mutations in the DNA-binding domain
of TP63, a region critical for direct interactions
with DNA target sequences
4. Genotype–phenotype correlation
a. 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
(Van Bokhoven et al. 2001)
b. Emerging paradigm for genotype–phenotype
correlation (Clements et al. 2010)
i. EEC syndrome, the prototype of all TP63
ectodermal dysplasia disorders, is the most
prevalent syndrome resulting from mutations
in the TP63 gene (Brunner et al. 2002;
Bougeard et al. 2003) with more than 200
cases reported in the literature
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 elim-
ination of excess cells during fusion of the arche-
typal plate
H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_77,# Springer Science+Business Media, LLC 2012
699
Clinical Features
1. Significant intra/interfamilial variability (Bigata
et al. 2003)
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
4. Ectodermal dysplasia (77%): may exhibit the fol-
lowing 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 suscepti-
bility 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 hypogonat-
dotropic hypogonadism and central diabetes
insipidus
c. Isolated absent septum pellucidum
10. Phenotype overlapping with split hand/foot
malformations
11. TP63-associated disorders (Clements et al. 2010):
Clinical features overlap with EEC syndrome,
although several distinct characteristics may help
distinguish them
a. AEC (ankyloblepharon, ectodermal dysplasia,
clefting) (Hay–Wells) syndrome (McGrath
et al. 2001): Typical features include:
i. Ankyloblepharon filiforme (partial eyelid
fusion)
ii. Skin erosions are typical features
b. ADULT (acro, dermato, ungula, lacrimal,
tooth) syndrome (Chan et al. 2004): Common
features include:
i. Mammary gland ⁄nipple hypoplasia
ii. An absence of clefting
iii. Increased skin freckling
c. Rapp–Hodgkin syndrome (Bougeard et al. 2003;
Chan et al. 2005): Typical features include:
i. Similar to AEC syndrome
ii. Usually an absence of ankyloblepharon
iii. Characteristic facies with midfacial hypo-
plasia and microstomia
d. Limb-mammary syndrome (Van Bolhoven
et al. 1999)
i. Similar limb defects to those seen in EEC
syndrome, including absence or severe
hypoplasia of digits and fusion ⁄separation
defects such as syndactyly
ii. Additional clinical features
a) Mammary gland ⁄nipple hypoplasia
b) Cleft palate only and limited
c) No skin or hair abnormalities
Diagnostic Investigations
1. Ophthalmologic evaluation for tear duct obstruction
2. Early audiological assessment
3. Renal ultrasound for associate renal anomalies
4. Radiographic evaluation for ectrodactyly
5. 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 (Bigata
et al. 2003)
6. Direct molecular analysis is possible for EEC
(TP63-related disorders) (www.genetests.org)
700 Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome
Genetic Counseling
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%
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
(South et al. 2002)
i. On fetal DNA extracted from CVS and
amniocytes by direct sequencing and restric-
tion endonucleases digestion (loss of AciI site
on mutant allele)
ii. Using a preimplantation genetic diagnostic
approach
3. Management (Bigata et al. 2003)
a. Supportive (multidisciplinary team approach)
i. Artificial tear for tear duct blockage
ii. Anticipate recurrent ophthalmologic infections
iii. Periodic odontologic management to pre-
vent 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. (2003). EEC
syndrome type 3 with a heterozygous germline mutation in
the P63 gene and B cell lymphoma. American Journal ofMedical Genetics, 120A, 370–373.
Anneren, G., Andersson, T., Lindgren, P. G., et al. (1991).
Ectrodactyly-ectodermal dysplasia-clefting syndrome
(EEC): The clinical variation and prenatal diagnosis.ClinicalGenetics, 40, 2570262.
Barrow, L. L., van Bokhoven, H., Daack-Hirsch, S., et al. (2002).
Analysis of the p63 gene in classical EEC syndrome, related
syndromes, and non-syndromic orofacial clefts. Journal ofMedical Genetics, 39, 559–566.
Bigata, X., Bielsa, I., Artigas, M., et al. (2003). The ectrodactyly-
ectodermal dysplasia-clefting syndrome (EEC): Report of
five cases. Pediatric Dermatology, 20, 113–118.Bixler, D., Spivack, J., Bennett, J., et al. (1972). The
ectrodactyly-ectodermal dysplasia-clefting (EEC) syn-
drome. Report of 2 cases and review of the literature.ClinicalGenetics, 3, 43–51.
Bougeard, G., Hadj-Rabia, S., & Faivre, L. (2003). The
Rapp–Hodgkin syndrome results from mutations of the TP63
gene. European Journal of Human Genetics, 11, 700–704.Bronshtein, M., & Gershoni-Baruch, R. (1993). Prenatal
transvaginal diagnosis of the ectrodactyly, ectodermal dys-
plasia, cleft palate (EEC) syndrome. Prenatal Diagnosis, 13,519–522.
Brunner, H. G., Hamel, B. C., & van Bokhoven, H. (2002). P63
gene mutations and human developmental syndromes.
American Journal of Medical Genetics, 112, 284–290.Buss, F. W., Hughes, H. E., & Clarke, A. (1995). Twenty-four
cases of the EEC syndrome: Clinical presentation and man-
agement. Journal of Medical Genetics, 32, 716–723.Celli, J., Duijf, P., Hamel, B. C., et al. (1999). Heterozygous
germline mutations in the p53 homolog p63 are the cause of
EEC syndrome. Cell, 99, 143–153.Chan, I., Harper, J. I., Mellerio, J. E., et al. (2004). ADULT
ectodermal dysplasia syndrome resulting from the missense
mutation R298Q in the p63 gene. Clinical and ExperimentalDermatology, 29, 669–672.
Chan, I., McGrath, J. A., & Kivirikko, S. (2005). Rapp–Hodgkin
syndrome and the tail of p63. Clinical and ExperimentalDermatology, 30, 183–186.
Clements, S. E., Techanukul, T., Coman, D., et al. (2010).
Molecular basis of EEC (ectrodactyly, ectodermal dysplasia,
clefting) syndrome: Five new mutations in the DNA-binding
domain of the TP63 gene and genotype-phenotype correla-
tion. British Journal of Dermatology, 162, 201–207.Crackower, M. A., Scherer, S.W., Rommens, J. M., et al. (1996).
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. HumanMolecular Genetics, 5, 571–579.
Kosaki, R., Ohashi, H., Yoshihashi, H., et al. (2001). A de novomutation (R279C) in the P63 gene in a patient with EEC
syndrome. Clinical Genetics, 60, 314–315.McGrath, J. A., Duijf, P. H., Doetsch, V., et al. (2001).
Hay-Wells syndrome is caused by heterozygous missense
mutations in the SAM domain of p63. Human MolecularGenetics, 10, 221–229.
Nardi, A. C., & Ferreira, U. (1992). Netto Junior NR: Urinary
tract involvement in EEC syndrome: A clinically study in 25
Brazilian patients. American Journal of Medical Genetics,44, 803–806.
O’Quinn, J. R., Hennekam, R. C., Jorde, L. B., et al. (1992).
Syndromic ectrodactyly with severe limb, ectodermal,
Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome 701
urogenital, and palatal defects maps to chromosome 19.
American Journal of Medical Genetics, 62, 130–135.Penchaszadeh, V. B., & de Negrotti, T. C. (1976). Ectrodactyly-
ectodermal dysplasia-clefting (EEC) syndrome: Dominant
inheritance and variable expression. Journal of MedicalGenetics, 13, 281–284.
Qumsiyeh, M. B. (1992). EEC syndrome (ectrodactyly, ectoder-
mal dysplasia and left lip/palate) is on 7p11.2-q21.3. ClinicalGenetics, 42, 101.
Rodini, E. S., & Richieri-Costa, A. (1990). EEC syndrome:
Report on 20 new patients, clinical and genetic consider-
ations. American Journal of Medical Genetics, 37, 42–53.Roelfsema, N. M., & Cobben, J. M. (1996). The EEC syndrome:
A literature study. Clinical Dysmorphology, 5, 115–127.Rollnick, B. R., &Hoo, J. J. (1998). Genitourinary anomalies are
a component manifestation in the ectodermal dysplasia,
ectrodactyly, cleft lip/palate (EEC) syndrome. AmericanJournal of Medical Genetics, 29, 131–135.
Scherer, S. W., Poorkaj, P., Massa, H., et al. (1994). Physical
mapping of the split hand/split foot locus on chromosome 7
and implication in Syndromic ectrodactyly. Human Molecu-lar Genetics, 3, 1345–1354.
South, A. P., Ashton, G. H., Willoughby, C., et al. (2002). EEC
(Ectrodactyly, Ectodermal dysplasia, Clefting) syndrome:
Heterozygous mutation in the p63 gene (R279H) and DNA-
based prenatal diagnosis. British Journal of Dermatology,146, 216–220.
Tse, K., Temple, I. K., & Baraitser, M. (1990). Dilemmas in
counseling: The EC syndrome. Journal of Medical Genetics,27, 752–755.
Van Bokhoven, H., Hamel, B. C. J., Bamshad, M., et al. (2001).
p63 gene mutations in EEC syndrome, Limb-Mammary
syndrome, and isolated split hand-split foot malformation
suggest a genotype-phenotype correlation. American Journalof Human Genetics, 69, 481–492.
Van Bolhoven, H., Jung, M., Smits, A. P., et al. (1999). Limb
mammary syndrome: A new genetic disorder with mammary
hypoplasia, ectrodactyly, and other hand/foot anomalies
maps to human chromosome 3q27. American Journal ofHuman Genetics, 64, 538–546.
Van Maldergem, L., Gillerot, Y., Vamos, E., et al. (1992).
Vasopressin and gonadotropin deficiency in a boy with the
ectrodactyly-ectodermal dysplasia-clefting syndrome. ActaPaediatrica, 81, 365–367.
Wessagowit, V., Mellerio, J. E., Pembroke, A. C., et al. (2000).
Heterozygous germline missense mutation in the p63 gene
underlying EEC syndrome. Clinical and ExperimentalDermatology, 25, 441–443.
702 Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome
Fig. 1 A stillborn with severe EEC syndrome
Fig. 2 An infant with EEC syndrome
a
b
c
Fig. 3 (a–c) An infant with EEC syndrome
Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome 703