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Clinical and Genetic Characterization of Frontorhiny: Report of 3 Novel

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Clinical and Genetic Characterization of Frontorhiny: Report of 3 Novel ORIGINAL ARTICLE Clinical and Genetic Characterization of Frontorhiny Report of 3 Novel Cases and Discussion of the Surgical Management Nguyen S. Pham, MD; Amir Rafii, MD; Jia Liu; Simeon A. Boyadjiev, MD; Travis T. Tollefson, MD Objectives: To (1) define the nasal, columellar, and lip Results: Patients 1 and 2 were brothers from the same deformities of 3 patients with characteristics consistent family. Both exhibited bifidity of their columella, a wid- with frontorhiny; (2) illustrate the embryologic correla- ened philtrum, poor nasal tip development, and low hair- tion of the oronasal findings to the development of the lines. Genetic sequencing in the 2 brothers confirmed the median nasal prominence; (3) report the clinical mani- presence of a novel ALX3 homeobox mutation at the sec- festation in 3 patients from 2 unrelated families; (4) re- ond exon (mutation Y214X). Patient 3 was a 4-year-old port a novel Y214X mutation in ALX3; and (5) describe girl. She presented with an underdeveloped, widened na- the surgical reconstruction. sal tip and a bifid columella. Her philtrum was widened and had a left-sided cartilaginous prominence. She also Methods: In this case series, we report 3 novel cases of had a widened nasal root. Family history revealed no fam- frontorhiny from 2 different families. The surgical re- ily members with the same features. construction technique is reviewed. Extension of the colu- mellar medial crural cartilage into the upper lip cleft is Conclusions: Frontorhiny represents a new syndromic examined histologically. Signed consent was granted for frontonasal malformation with consistent characteristic all patient photographs and specimens, and the study was features. The genetic abnormality has now been found approved by the institutional review committee of the Uni- in 14 different patients. Careful scrutiny and classifica- versity of California Davis The genetic sequencing of the tion of frontonasal deformities will expand our under- ALX3 homeobox gene was performed in 2 of our 3 cases standing of causes, genetic susceptibility, and treatment using standard commercially available sequencing kits. options. The genetic material in our third case was not available for analysis. Arch Facial Plast Surg. 2011;13(6):415-420 MBRYOLOGY IS A HIGHLY CHO- define frontonasal malformation include reographed dance in which at least 2 of the following characteristics: multiple parts must em- hypertelorism, broad nasal root, median brace, move, and grow in facial clefting, nasal alar clefting, mal- perfect synchrony. The tis- formed nasal tip, anterior cranium bif- Esues that move most closely together, that idum occultum or a V-shaped hair pat- respond and react to the same stimuli, are tern on the forehead (Figure 1). embryonic subunits called developmental Median oronasal clefts are rare defor- fields. Any misstep in embryogenesis, mities that likely arise from the incom- therefore, results in a chain reaction that plete fusion of the paired median nasal affects the entire developmental field in prominences during embryologic devel- predictable patterns. opment. When they are less severe, these Author Affiliations: One such pattern is a series of anoma- clefts are often seen in conjunction with Department of lies called frontonasal malformations, rare hypertelorism and normal brain develop- Otolaryngology–Head and Neck craniofacial defects thought to arise from ment. Meanwhile, the other end of the Surgery (Drs Pham and the abnormal development of the fronto- spectrum includes the various forms of ho- Tollefson) and Section of nasal prominence. As described by Se- loprosencephaly (the most severe being cy- Genetics, Department of dano and Gorlin,1 frontonasal malforma- clopia with hypotelorism). Many classifi- Pediatrics (Ms Liu and tion describes a type of developmental field cation systems have been proposed, Dr Boyadjiev), University of 2 California, Davis Medical defect in which the root cause is believed including that of DeMyer, who pro- Center, Sacramento; and Kaiser to be abnormal development of the fron- posed the term holoprosencephaly in 1967. Permanente, San Francisco, tonasal prominence in craniofacial em- In addition, these deformities have been California (Dr Rafii). bryogenesis. The features that are used to classified as Tessier type 0 and type 14 ARCH FACIAL PLAST SURG/ VOL 13 (NO. 6), NOV/DEC 2011 WWW.ARCHFACIAL.COM 415 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 nized around the primitive mouth—the stomodeum (Figure 2). They consist of a single frontonasal promi- nence and paired maxillary and mandibular promi- nences. The frontonasal prominence surrounds the ventrolateral part of the forebrain and forms the upper border of the stomodeum.4 The maxillary and man- dibular prominences are derived from the first pair of pharyngeal arches and form the lateral and caudal bor- ders of the stomodeum, respectively. Midline merging of the medial nasal prominences leads to formation of the upper lip tubercle and philtrum, the nasal tip, pri- mary palate, and premaxilla.5 The lateral portions of the upper lip, the bulk of the maxilla, and the secondary palate are formed by the maxillary prominences. Lateral unions of the maxillary and mandibular prominences Figure 1. Photograph of a child with typical features of frontonasal 5 malformation (not frontorhiny), as defined by Sedano and Gorlin,1 including create the oral commissures. 6 7 at least 2 of the following: true ocular hypertelorism, broadening of nasal Twigg et al and Lees et al have described a unique root, median facial cleft, lack of formation of nasal tip, cranium bifidum frontonasal malformation they termed frontorhiny, a new occultum, V-shaped frontal hairline, and/or alar cleft. autosomal recessive syndrome characterized as a distinc- tive disease entity falling within the spectrum of fronto- nasal malformations. Twigg et al6 reported 3 cases pre- A B senting with the classic features. In the same study, a causative ALX3 homeobox gene (OMIM 136760) for frontorhiny was identified. Lees et al7 described 2 addi- tional patients with the same clinical features and the same genetic mutation. The syndrome was described in 11 dif- ferent patients from 7 families, and is characterized by hypertelorism, wide nasal bridge, bifid nasal tip, broad columella, widely separated narrow nares, long phil- trum, and bilateral nasal swellings. In addition, a ge- netic study of the 11 patients with the clinical features of frontorhiny revealed 7 distinct gene mutations in the same ALX3 homeobox gene.6,7 In the present study, we describe 3 patients with clini- cal findings consistent with the distinct features of fron- torhiny. The purpose of this study is to present the char- Figure 2. Color-coded developmental fields. A, In week 6 of embryogenesis, yellow indicates the frontonasal prominence; brown, maxillary processes; acteristics of our 3 patients with this unique frontonasal blue. the mandibular arch; green, median nasal processes; and purple, lateral malformation and the techniques used for surgical re- nasal processes. B, Color-coded illustration of patient 1 shows the construction. embryologic derivation of his facial structures. METHODS clefts.3 The terms frontonasal dysplasia and frontonasal malformation were introduced by Sedano and Gorlin1 to emphasize that the continuum of median facial defor- Herein, we report 3 novel cases of frontorhiny occurring in pa- mities represents a developmental field defect. Most of tients from 2 different families. The surgical reconstruction tech- the various median facial deformities are sporadic and nique is reviewed. Histologic analysis of soft-tissue extension have multiple etiologic factors; however, familial cases of the columellar medial crural cartilage into the upper lip is examined. and syndromic associations have also been reported. In Sequencing of the ALX3 homeobox gene was performed in the case of frontonasal malformations, the persistence of 2 of our 3 cases. All patient photographs and specimens were the frontonasal process in its embryogenic position keeps obtained only after signed consents, and the study was ap- the orbits from reaching their normal position. This is proved by the institutional review committee of University of thought to cause the distinct hypertelorism and midline California, Davis. The DNA of our third case was not available abnormalities such as clefting of the lip and nose.1 Em- for analysis. bryologic development of the face is also closely related Total lymphocyte DNA from the affected brothers and their to forebrain development through the frontonasal promi- parents was extracted and purified using a standard DNA ex- nence, which gives rise to the paired medial nasal promi- traction kit (Qiagen Inc, Valencia, California) in accordance with the manufacturer’s instructions. Primer sequences based nences, as shown in Figure 2. on GenBank accession code NG_012039.1 were designed to am- The 5 facial primordia are formed by the prolifera- plify the complete coding region of ALX3, including the 5Ј- and tion of neural crest cells. During the fourth week of de- 3Ј- untranslated regions. Direct forward and reverse sequenc- velopment, these cells migrate ventrolaterally from ing was carried out by the dideoxy chain termination method their initial dorsal location to populate mesenchyme of with the Sequenase, version 2.0, DNA sequencing kit (US Bio- the facial primordia (The 5 facial prominences are orga- chemical, Cleveland,
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