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Disease Profile

Facial ectodermal dysplasia

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Neonatal

ICD-10

Q82.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Setleis syndrome; Bitemporal forceps marks syndrome; Focal facial dermal dysplasia type 2;

Categories

Congenital and Genetic Diseases; Skin Diseases

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 1807

Definition
Focal facial dermal dysplasia type III (FFDD3) is a rare focal facial dermal dysplasia (FFDD; see this term), characterized primarily by congenital bitemporal scar-like depressions and a typical, but variable facial dysmorphism, which may include distichiasis (upper lids) or lacking eyelashes, slanted eyebrows and a flattened and/or bulbous nasal tip and other features such as a low frontal hairline, sparse hair, redundant skin, epicanthal folds, low-set dysplastic ears, blepharitis and conjunctivitis.

Epidemiology
FFDD3 is reported in over 20 patients from more than 15 families, but only 4 consanguineous families have had TWIST2 mutations.

Clinical description
FFDD3 is characterized by congenital bitemporal hypoplastic scar-like lesions resembling forceps marks with typical facial dysmorphic features. In addition, they may have periorbital puffiness (leonine facies), sparse lateral and upward lifting eyebrows, distichiasis (upper lashes), a lack of lower lashes and a prominent upper lip (with an inverted ''V'' contour). Nose abnormalities are very frequent and comprise a flattened and/or bulbous nasal tip with septum extended below the alae nasi. Additional frequent features describe a low frontal hairline, sparse hair, epicanthal folds, blepharitis, conjunctivitis, low-set dysplastic ears, and redundant skin. Other eye abnormalities less often reported include short and/or slanting palpebral fissures, as well as impaired vision, nystagmus, exotropia, hypertelorism and absent meibomian glands. Skin dimples lateral to lips, vertical chin clefts, horizontal chin furrows and linear grooves on forehead occur occasionally. Other features such as a pectum deformities and cardiac and genitorurinary abnormalities are rare. Patients generally have normal growth and development. Heterozygous family members may present with minor manifestations, such as partial absence of lower eyelashes and distichiasis of upper lashes. Developmental delay, severe intellectual disability, behavioral problems, and learning difficulties may be observed.

Etiology
FFDD3 is caused by homozygous mutations in the TWIST2 gene, which encodes a bHLH transcription factor involved in dermal facial development in mammals. To date two nonsense mutations, c.324C>T (p. Q65X) and c.486C>T (p.Q119X), and two small deletions that caused frameshift mutations, c.168delC (p.S57AfsX45) and c.91delC (p.R31GfsX71), have been reported. However, the majority of unrelated FFDD3 patients evaluated have had normal TWIST2 sequences, indicating the molecular genetic heterogeneity of the disorder. Studies are under way to interrogate whole exome or genome sequencing in these patients and their parents to determine the causative defects.

Diagnostic methods
FFDD3 is diagnosed in patients bearing autosomal recessive bitemporal scar-like lesions and typical FFDD3 facial features, and is confirmed by genetic testing of TWIST2. However, many patients with typical FFDD3 features have normal TWIST2 sequences (~80%). Thus, diagnosis is clinically based for most patients on the characteristic bitemporal lesions and facial dysmorphism regardless of inheritance. Also, the facial phenotype may be milder in patients without TWIST2 mutations.

Differential diagnosis
Differential diagnosis includes FFDD1 and FFDD2 (see these terms).

Genetic counseling
Many cases are sporadic. Inheritance is autosomal recessive for patients with TWIST2 mutations. Heterozygous parents will have a 1 in 4 risk of an affected child with each pregnancy. For other patients, the inheritance is unclear.

Management and treatment
Pursed lips and eye abnormalities may be surgically corrected, but there is limited experience with plastic surgery.

Prognosis
In patients with normal intelligence, normal life span is expected. Patients with developmental delay may have other organ system involvement which may affect health and longevity.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal hair pattern
Abnormal distribution of hair
0010720
Abnormality of the sacroiliac joint
0100781
Aplasia/Hypoplasia of the skin
Absent/small skin
Absent/underdeveloped skin

[ more ]

0008065
Depressed nasal ridge
Flat nose
Recessed nasal ridge

[ more ]

0000457
Dimple chin
Chin butt
Chin dent
Chin dimple
Chin skin dimple
Indentation of chin

[ more ]

0010751
Downturned corners of mouth
Downturned corners of the mouth
Downturned mouth

[ more ]

0002714
Prematurely aged appearance
Precociously senile appearance
0007495
Redundant skin
Loose redundant skin
Redundant skin folds
Sagging, redundant skin

[ more ]

0001582
30%-79% of people have these symptoms
Abnormality of the upper urinary tract
0010935
Anal atresia
Absent anus
0002023
Distichiasis
0009743
Epicanthus
Prominent eye folds
Eye folds

[ more ]

0000286
Highly arched eyebrow
Arched eyebrows
Broad, arched eyebrows
High, rounded eyebrows
High-arched eyebrows
Thick, flared eyebrows

[ more ]

0002553
Short philtrum
0000322
Sparse lateral eyebrow
Limited hair on end of eyebrow
0005338
Sparse lower eyelashes
Scanty lower eyelashes
Thin lower eyelashes

[ more ]

0007776
Wide nasal bridge
Broad nasal bridge
Broad nasal root
Broadened nasal bridge
Increased breadth of bridge of nose
Increased breadth of nasal bridge
Increased width of bridge of nose
Increased width of nasal bridge
Nasal bridge broad
Wide bridge of nose
Widened nasal bridge

[ more ]

0000431
5%-29% of people have these symptoms
Downslanted palpebral fissures
Downward slanting of the opening between the eyelids
0000494
Hypopigmented skin patches
Patchy loss of skin color
0001053
Lacrimation abnormality
Abnormality of tear production
0000632
Multiple cafe-au-lait spots
0007565
Strabismus
Cross-eyed
Squint
Squint eyes

[ more ]

0000486
1%-4% of people have these symptoms
Bitemporal forceps marks
0011336
Bulbous nose
0000414
Chin with horizontal crease
Chin with horizontal groove
Horizontal chin skin cleft

[ more ]

0011823
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root

[ more ]

0005280
Low anterior hairline
Low frontal hairline
Low-set frontal hairline

[ more ]

0000294
Periorbital fullness
Puffiness around eye
0000629
Thick upper lip vermilion
Full upper lip
Increased volume of upper lip
Plump upper lip
Prominent upper lip
Thick upper lip

[ more ]

0000215
Percent of people who have these symptoms is not available through HPO
Absent lower eyelashes
Failure of development of lower eyelashes
0007646
Aged leonine appearance
0008509
Autosomal recessive inheritance
0000007
Sparse hair
0008070

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

      In-Depth Information

      • Medscape Reference provides information on ectodermal dysplasias. You may need to register to view the medical textbook, but registration is free
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Facial ectodermal dysplasia. Click on the link to view a sample search on this topic.