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

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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