Focal facial dermal dysplasia type III (ORPHA:1807)
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.

                            Last update: 
                            June 2014


                            - Expert reviewer(s): 
                            Dr Robert DESNICK  - Dr Beomhee LEE