Cleft Lip/palate-Ectodermal Dysplasia syndrome (CLPED1)

What is Cleft Lip/palate-Ectodermal Dysplasia syndrome (CLPED1)?

EEC syndrome is a rare genetic condition that presents with 3 specific congenital defects or symptoms.

These symptoms affect the skin, hands and feet and lip/mouth of affected individuals.

The syndrome was first documented in 1770 in South America.

Syndrome Synonyms:
CLPED1 Ectodermal Dysplasia, Cleft Lip And Palate, Mental Retardation, And Syndactyly Ectodermal Dysplasia, Margarita Island Type Ectodermal Dysplasia, Type 4; Ed4 Margarita Island ectodermal dysplasia Zlotogora-ogur Syndrome

What gene changes cause Cleft Lip/palate-Ectodermal Dysplasia syndrome (CLPED1)?

Mutations in the TP63 gene are responsible for causing the syndrome. It is inherited in an autosomal dominant pattern.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

What are the main symptoms of Cleft Lip/palate-Ectodermal Dysplasia syndrome (CLPED1)?

the 3 main features of this rare disease are:

1. Ectrodactyly: this leads to lobster-claw hands and feet
2. Ectodermic dysplasia: fine, short hair, absent eyebrows and eyelashes, nails that do not develop properly
3. Cleft lip, with or without a cleft palate

Other symptoms or features associated with the syndrome include intellectual disability, midface hypoplasia, hypopigmentation of the skin, hearing loss, a short stature, blindness and nipple abnormalities

Possible clinical traits/features:
Malar flattening, Downslanted palpebral fissures, Ectodermal dysplasia, Cleft upper lip, Cutaneous syndactyly of toes, Cutaneous finger syndactyly, Finger syndactyly, EEG abnormality, Abnormal fingernail morphology, Abnormality of the ear, Abnormal toenail morphology, Abnormal nipple morphology, Abnormality of the ureter, Abnormality of the philtrum, Carious teeth, Wide nasal bridge, Nail dysplasia, Alopecia, Anodontia, Cleft palate, Neurological speech impairment, Abnormality of hair texture, Abnormality of dental morphology, Abnormality of dental enamel, Micrognathia, Microdontia, Macrotia, Sparse lateral eyebrow, Reduced number of teeth, Triangular face, Recurrent respiratory infections, Sparse and thin eyebrow, Synophrys, Pili torti, Scrotal hypoplasia, Autosomal recessive inheritance, Sparse eyelashes, Seizure, Single transverse palmar crease, Palmoplantar hyperkeratosis, Toe syndactyly, Progressive hypotrichosis, Hyperkeratosis, Hyperlordosis, Hypohidrosis, Hypodontia, Hypoplasia of the zygomatic bone

How does someone get tested for Cleft Lip/palate-Ectodermal Dysplasia syndrome (CLPED1)?

The initial testing for Cleft Lip/palate-Ectodermal Dysplasia syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Cleft Lip/palate-Ectodermal Dysplasia syndrome (CLPED1)

Syndrome Overview:
Cleft lip/palate-ectodermal dysplasia syndrome is characterized by cleft lip and palate, cutaneous syndactyly of the fingers and/or toes, trichodysplasia, onychodysplasia, teeth dysplasia and ear anomalies. Hypohidrosis, palmoplantar hyperkeratosis, intellectual disability, malar hypoplasia and deafness may also be features. The autosomal recessive disorder is caused by homozygous mutations in the NECTIN1 gene.

Clinical Description:
Almost simultaneously in separate journals, Zlotogora et al., (1987) and Martinez et al., (1987) described children with cleft lip and palate, malformed ears, pili torti, partial syndactyly of the digits and intellectual disability.

Zlotogora et al., (1987) described sisters - the offspring of first cousins - with intellectual disability.

Martinez et al., (1987) described an isolated female case with an IQ of 85. Her mother had mild dysmorphic features including small teeth and mildly coarse scalp hair. Autosomal or X-linked dominant inheritance was inferred, but this is far from certain.

Ogur and Yuksel (1988) described two Turkish brothers, again the offspring of first cousins, with a similar condition.

The large inbred pedigree from Margarita, Venezuela, reported by Bustos et al., (1991) appears to be segregating for a very similar condition. The main difference from other reports is a lack of intellectual disability in affected individuals.

Richieri-Costa et al., (1992) reported another 23-year-old female who possibly had the same condition. She had normal intelligence. The parents were first cousins, and three previous sibs who died in the neonatal period were reported to have cleft lip and palate.

Zlotogora (1994) provides a review of the condition. He does not agree that the case reported by Martinez et al., (1987) has the same condition, but this seems debatable.

Atasu et al., (2001) reported a 19-year-old girl with almost complete absence of scalp and body hair, oligodontia, conically maxillary central incisors, and zygodactyly of the palmar triradii suggesting a form of syndactyly type I. There was no cleft lip or palate.

Fodor et al., (2006) reported an isolated patient with bilateral cleft lip, bilateral cutaneous syndactyly of the 2nd and 3rd toes, high frontal hairline, and developmental delay. This patient may also have had blepharocheilodontic syndrome, as there was also lagophthalmos, everted lower lip and hypothyroidism.. The patient had several periorbital dermoid cysts, which have also been reported on the scalp in blepharocheilodontic syndrome.

Yoshida et al., (2015) reviewed the clinical features of patients reported to date with confirmed mutations in the NECTIN1/PVRL1 gene. All had cleft lip and palate, cutaneous syndactyly of the fingers and/or toes, trichodysplasia, onychodysplasia, teeth dysplasia and ear anomalies. Hypohidrosis, palmoplantar hyperkeratosis, intellectual disability, malar hypoplasia and deafness were reported in some of the cases.

Molecular genetics:
Suzuki et al., (1998) mapped the gene to 11q23 in the family reported by Bustos et al., (1991).

Suzuki et al., (2000) studied four families from Margarita Island and Israeli and Brazilian families with Zlotogora-Martinez syndrome. Homozygous mutations (W185X) were found in the PVRL1 gene, coding for nectin-1, an immunoglobulin (Ig)-related transmembrane cell-cell adhesion molecule that is part of the NAP cell adhesion system.

Sozen et al., (2001) reported a highly significant association between heterozygosity for the W185X mutation and non-syndromic cleft palate in Northern Venezuela but not on Margarita Island (although numbers were small).

Cheng et al., (2012) reviewed 45 SNPs in the NECTIN1 gene in 470 patients with non-syndromic cleft lip/palate and 693 controls. No SNPs were found to be associated with cleft lip/palate.

Yoshida et al., (2015) described a patient with homozygous protein-truncating mutations in the NECTIN1 gene. Clinical characteristics included intellectual disability, sparse hair and eyebrows, kinky hair, malar hypoplasia, concave nasal bridge, cleft lip/palate, teeth dysplasia and hypodontia, and low-set protruding ears. Additional features were hypohidrosis, palmoplantar hyperkeratosis, cutaneous syndactyly and onychodysplasia. Electronic microscopy of hair showed pili torti and pili trianguli et canaliculi.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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