True Midline Cleft Lip: Two Cases and Review of Genetics
Jacob Azurdia, BA
Donald Laub, MD, FACS
Leah Burke, MD, FAAP
Disclosures
I have no financial or nonfinancial relationships in the products or services described, reviewed, evaluated or compared in this presentation.
Introduction
Midline or median cleft lip is a rare type of cleft lip with an incidence amongst cleft patients of only 0.43 to 0.73%.
It is often accompanied by more significant midline malformations of the face and brain.
False vs. True Median Cleft
Median cleft lip is often divided into true and false median clefts.
The false median cleft lip referring to that seen in cases of holoprosencephaly where there is an absence of the midline tissue of the lip and nasal columella.
True median cleft lip is rare and may occur as part of a frontonasal dysplasia or be accompanied by dermoid cysts, encephalocele, or fibroepithelial skin tags.
True Median Cleft Lip
This type of cleft is also sometimes described according to the Tessier classification system as a “Tessier number 0 cleft”
The genetic and environmental mechanisms that affect the epithelial fusion and cause the traditional type of cleft lip are most likely not involved in the formation of a true median cleft lip as evidenced by a lack of visible epithelial bridging in the area forming the maxillary median groove.
Finally, median cleft lip is most often a sporadic event. However, case reports amongst families show affected individuals in multiple generations suggesting the possibility of an autosomal dominant or X-linked dominant inheritance pattern.
Upper Lip Formation
The structure of the upper lip is formed by the fusion of various processes that are derived from migrating neural crest cells; the medial nasal prominences (MNP) and lateral nasal prominences (LNP) and maxillary prominences (MXP).
The paired MNP forms the philtrum while the remainder of the upper lip tissue is supplied by the MXP.
Both epithelial-mesenchymal transformation and programmed cell death seem to be necessary for lip fusion and breakdown of the epithelial seam between the MNP, LNP, and MXP.
Upper Lip Formation
The closure of the groove between the paired MNP does not seem to involve active epithelial fusion but occurs as a result of continued growth and confluence of medial nasal and maxillary mesenchyme.
After the epithelial fusion of the MXP, LNP and MNP, the growth of the MXP pushes the nasal pits and MNP mediofrontally.
The growth of the midline and MNP tissues fills in the gap between the MNP in a posterior to anterior pattern causing the groove between the two MNP to become shallower and finally smooth.
Methods
We present the case histories of two children with incomplete true midline cleft lips and propose possible mechanisms for this rare malformation.
Patient 1: E.P.
Female patient with interrupted vermillion and a very mild incomplete midline cleft of the vermillion and lower philtrum of the lip.
She has preauricular skin tags, normal development and brain structure.
Patient 2: P.C.
Male with a midline cleft that involves the vermilion as well as the center of the philtrum.
He has a widened nasal tip, and a fibroepithelial skin tag in the midline of the cleft that on casual inspection would appear to be the prolabium of a bilateral cleft lip.
He has a lipoma of the interhemispheric fissure, and dysgenesis of the corpus callosum.
He has no abnormalities of development, however.
Mechanism 1: Wnt
The genetic orchestration of the formation of the upper lip is still being elucidated. Genes and molecular pathways that are involved in the regulation of neural crest formation, migration, patterning, proliferation, and apoptosis appear to be important players.
In the Wnt pathway, Wnt3 and Wnt9b are particularly expressed in the underlying mesenchyme of the MNP, LNP and MXP.
Wnt3 mRNA is specifically expressed in the distal MNP, therefore making this an attractive candidate gene for a true median cleft.
Because cleft patients often show a deficiency of mesenchymal tissue, it has been suggested that there may have been a decrease in the proliferation of the midline, MNP or MXP mesenchyme through an alteration of expression of the Wnt3 or other candidate gene.
Mechanism 2: Sonic Hedgehog
The natural median groove in a mouse’s upper lip is somewhat similar to the partial median clefts seen in our patients.
The order of the fusion of the various processes involved differs in mice compared to humans, and could have been altered in these patients.
Other studies in mice employing antagonists of the Hedgehog pathway to induce the formation of cleft lip (both lateral and median) have demonstrated that inhibition of Sonic Hedgehog results in the distal MNP lacking size and being of an irregular angle compared to normal.
This finding suggests the Hedgehog pathway as another important player in the development of the median cleft lip.
Mechanism 3: RALDH and RARγ
A recent study using the frog as an animal model examined the role of retinoic acid signaling in median cleft lip formation.
It was revealed that retinoic acid synthesis enzyme (RALDH) is expressed in the MNP and LNP while retinoic acid receptor gamma (RARγ) is expressed in the MNP and MXP of developing frog embryos.
By inhibiting the function of these entities, median clefts were induced in developing embryos.
Further, homeobox genes Msx2 and Lhx8 were shown to be regulated by RARγ.
When both RARγ and Msx2/Lhx8 are inhibited, median cleft lip was induced in 100% of test subjects.
Thus, retinoic acid signaling and homeobox genes Msx2 and Lhx8 may be added to the pool of potential players in the formation of a true median cleft.
Conclusion
A true midline cleft is distinct from a paramedian cleft and holoprosencephaly
The mechanisms by which the two types of clefts form are also distinct
The midline cleft is a rare event and most often sporadic, but some evidence suggests autosomal or X-linked inheritance
The following genes and pathways may be implicated in the formation of the midline cleft: Wnt, Sonic Hedgehog, RALDH and RARγ
Median clefts have good surgical outcome with straight-line repairs