EEC syndrome is an ectodermal dysplasia syndrome associ- ated 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 sup- pression. 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 malforma- tion 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
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
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 hypo- thalamic-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. 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
6. Direct molecular analysis is possible for EEC3 7. Linkage analysis for known EEC2 families
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%
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Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome
340 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
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EEC SYNDROME 341
Fig. 1. A stillborn with severe EEC syndrome.
Fig. 2. An infant with EEC syndrome.
Fig. 3. An infant with EEC syndrome.
