Frontonasal Dysplasia Research Articles

Bifid nose – A mild degree of frontonasal dysplasia. A case report

Frontonasal dysplasia is an unusual congenital condition with a wide phenotypic range. Because of this, only a small number of cases and their management have been reported in the literature. The ideal surgical procedures to correct mild cases of frontonasal dysplasia, and the time to perform them, are still controversial. The case of a 9-month-old girl with a mild form of this condition (a congenital bifid nose and a duplicated frenulum), and its surgical management, is presented. The surgery achieved an early improvement of the patient's appearance and she had no complications. In the future, it is probable that she will need secondary rhinoplasty to aid in the projection of the tip and refine the shape of the nose.

Oculoauriculofrontonasal syndrome: Case series revealing new bony nasal anomalies in an old syndrome

Frontonasal Dysplasia (FND) and Oculo-auriculo-vertebral spectrum (OAVS) are two well-recognized clinical entities. With features of both FND and OAVS, the term oculoauriculofrontonasal syndrome (OAFNS) was coined in 1981. The OAFNS phenotype combines elements of abnormal morphogenesis of the frontonasal and maxillary process (derived from forebrain neural crest) with abnormal development of the first and second branchial arches (derived from hindbrain neural crest). We present a case series of 33 children with OAFNS ascertained from a comprehensive review of the literature and report an additional retrospective series of eight patients displaying features consistent with OAFNS. Notably, in a subset of our cases, we have observed abnormalities in nasal ossification and bony structures of the maxilla that have not previously described in OAFNS and are not seen in either FND or OAVS. We present the phenotype and novel naso-maxillary findings and explore potential etiologic and developmental pathways for OAFNS. We highlight the differences in phenotypic characteristics of OAFNS compared to OAVS and FND. These observations support the classification of OAFNS as a discrete syndrome. Further phenotypic refinements of OAFNS are needed to understand pathogenesis of this syndrome and the newly described nasal malformation may help identify the etiology.

Anterior interhemispheric calcified lipoma together with subcutaneous lipoma and agenesis of corpus callosum: a rare manifestation of midline craniofacial dysraphism

Frontonasal dysplasia (FND) or craniofacial dysraphism includes a variety of craniofacial defects. FNDs are rarely associated with intracranial lipoma. The majority of intracranial lipomas are incidentally identified on radiological examinations. They are commonly accompanied by other congenital intracranial malformations. Moreover, they are rarely associated with subcutaneous lipoma. We present a rare case of midline craniofacial dysraphism with interhemispheric calcified lipoma together with subcutaneous lipoma and agenesis of the corpus callosum.

Prenatal diagnosis of frontonasal dysplasia with anterior encephalocele

Frontonasal dysplasia is a rare congenital anomaly affecting the eyes, nose and forehead, and occurs sporadically in most of the cases. A 24-year-old woman was referred to our unit at 27 weeks gestation due to the preliminary diagnosis of encephalocele. The sagittal and axial sonography of the fetal face depicted a midline mass measuring 3.8 × 4.2 cm, projecting anteriorly between the fetal orbits and extending from the the upper aspects of the forehead to the nasal bridge, which was consistent with the frontal (anterior) encephalocele. There were prominent hypertelorism and two facial clefts, and the nostrils were extremely separated. Following genetic counseling, the couple requested termination of pregnancy. Fetal pathologic examination confirmed the diagnosis of frontonasal dysplasia and anterior encephalocele with no additional major malformation. The fetal karyotype was normal and no mutation in the ALX1 gene was found, excluding ALX1-related frontonasal dysplasia in the differential diagnosis. Fetuses with neural tube defect may suffer from associated syndromes and disorders, as with our case. The presence of frontonasal dyplasia should be considered when an anterior encephalocele is detected by ultrasonography.

Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation

Frontonasal dysplasias (FND) comprise a spectrum of disorders caused by abnormal median facial development. Its etiology is still poorly understood but recently frontonasal dysplasia phenotypes were linked to loss-of-function mutations in the ALX homeobox gene family, which comprises the ALX1, ALX3, and ALX4 genes. All ALX-related frontonasal phenotypes till date had been compatible with an autosomal recessive mode of inheritance. In contrast, heterozygous loss-of-function mutations in ALX4 had been only associated with isolated symmetrical parietal ossification defects at the intersection of the sagittal and lambdoid sutures, known as enlarged parietal foramina. We report a family with vertical transmission from mother to son of mild frontonasal dysplasia phenotype caused by a novel ALX4 gene mutation (c.1080-1089_delGACCCGGTGCinsCTAAGATCTCAACAGAGATGGCAACT, p.Asp326fsX21).This is the first report of a frontonasal phenotype related to a heterozygous mutation in ALX4. This mutation is predicted to cause the loss of the aristaless domain in the C-terminal region of the protein and preserves the homeodomain. We speculate that a different mechanism, a dominant-negative effect, is responsible for the distinct phenotype in this family.

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries—a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5′ untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5′ UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.

Etiology and genetic factors in clefts of lip and/or palate reported at children′s hospital, Lahore, Pakistan

The etiology of cleft lip (CL) and/or cleft palate (CP) has been extensively studied in industrialized countries and is suggested to be heterogeneous with increasing evidence that both genetic and environmental factors are operating. To evaluate this assertion in a developing country like Pakistan, a case finding cross-sectional study was completed from 1st July 2010 to 31st May 2011 for 100 cases of CL and/or CP referred to the Genetic Clinic of the Children’s Hospital, Lahore, Pakistan. A clinical examination followed by necessary diagnostic work-up was completed for each case. The cause of CL and/or CP was clear in 18% of the children (n = 18). Environmental causes were found in 6 children (four mothers developed hyperthermia during the 2nd month of gestation, one mother was diabetic, and one mother was a known case of epilepsy and took sodium valproate throughout her pregnancy). Six children were suffering from known genetic malformation syndromes (each with Jarcho-Levin syndrome, Oral-Facial-Digital syndrome type XI, Oral-Duplication syndrome, Kabuki syndrome, Fronto-nasal dysplasia and Nager syndrome). Novel chromosomal aberrations were identified in 2 children. In 82% of the children (n = 82) the cause of oro-facial clefts remained unknown. Impact of gender and consanguinity on the development of CL and/or CP was also studied. Prevalence of CP was significantly more among female children as compared to that in males (P < 0.05). Associated anomalies were present in 18% of the cases, anomalies of the craniofacial region being the most common. These findings were compared with regional and international studies.

Using bioabsorbable fixation systems in the treatment of pediatric skull deformities leads to good outcomes and low morbidity

Bioabsorbable fixation systems have been widely employed in pediatric patients for cranial reconstruction, obviating the complications of hardware migration and imaging artifact occurring with metallic implants. Recent concern over complications unique to bioabsorbable materials, such as inflammatory reaction and incomplete resorption, necessitates additional conclusive studies to further validate their use in pediatric neurosurgery and craniofacial surgery. Likewise, long-term follow-up in this clinical cohort has not previously been described. We included consecutive pediatric patients under the age of 2, from Lucile Packard Children's Hospital, who underwent cranial vault reconstruction with the use of a bioabsorbable fixation system between 2003 and 2010. Hospital records were queried for patient characteristics, intraoperative data, and postoperative complications. Ninety-five patients with the following preoperative pathologies were analyzed: craniosynostosis (87), cloverleaf skull (5), frontonasal dysplasia (1), and frontonasal encephalocele (2). Median age was 6 months (range 1-24 months). Average case duration was 204 minutes (range 40-392 min), with median of 154 mL blood loss (range 30-500 mL). Ninety-three percent of patients had 1-4 plates implanted with 48% receiving three plates. The median number of screws used was 59 (range 0-130). The median length of hospital stay was 4 days (range 2-127 days) with an average follow-up of 22 months (five postoperative visits). The complications related to hardware implantation included swelling (1%) and broken hardware (1%), the latter of which required reoperation. The bioabsorbable fixation systems for cranial vault reconstruction in children less than 2 years of age is safe with tolerable morbidity rates.

Defective neural crest migration revealed by a Zebrafish model of Alx1-related frontonasal dysplasia

Frontonasal dysplasia (FND) refers to a class of midline facial malformations caused by abnormal development of the facial primordia. The term encompasses a spectrum of severities but characteristic features include combinations of ocular hypertelorism, malformations of the nose and forehead and clefting of the facial midline. Several recent studies have drawn attention to the importance of Alx homeobox transcription factors during craniofacial development. Most notably, loss of Alx1 has devastating consequences resulting in severe orofacial clefting and extreme microphthalmia. In contrast, mutations of Alx3 or Alx4 cause milder forms of FND. Whilst Alx1, Alx3 and Alx4 are all known to be expressed in the facial mesenchyme of vertebrate embryos, little is known about the function of these proteins during development. Here, we report the establishment of a zebrafish model of Alx-related FND. Morpholino knock-down of zebrafish alx1 expression causes a profound craniofacial phenotype including loss of the facial cartilages and defective ocular development. We demonstrate for the first time that Alx1 plays a crucial role in regulating the migration of cranial neural crest (CNC) cells into the frontonasal primordia. Abnormal neural crest migration is coincident with aberrant expression of foxd3 and sox10, two genes previously suggested to play key roles during neural crest development, including migration, differentiation and the maintenance of progenitor cells. This novel function is specific to Alx1, and likely explains the marked clinical severity of Alx1 mutation within the spectrum of Alx-related FND.

A familial case with interstitial 2q36 deletion: Variable phenotypic expression in full and mosaic state

Submicroscopic chromosomal anomalies play an important role in the etiology of craniofacial malformations, including midline facial defects with hypertelorism (MFDH). MFDH is a common feature combination in several conditions, of which Frontonasal Dysplasia is the most frequently encountered manifestation; in most cases the etiology remains unknown. We identified a parent to child transmission of a 6.2 Mb interstitial deletion of chromosome region 2q36.1q36.3 by array-CGH and confirmed by FISH and microsatellite analysis. The patient and her mother both presented an MFDH phenotype although the phenotype in the mother was much milder than her daughter. Inspection of haplotype segregation within the family of 2q36.1 region suggests that the deletion arose on a chromosome derived from the maternal grandfather. Evidences based on FISH, microsatellite and array-CGH analysis point to a high frequency mosaicism for presence of a deleted region 2q36 occurring in blood of the mother. The frequency of mosaicism in other tissues could not be determined. We here suggest that the milder phenotype observed in the proband's mother can be explained by the mosaic state of the deletion. This most likely arose by an early embryonic deletion in the maternal embryo resulting in both gonadal and somatic mosaicism of two cell lines, with and without the deleted chromosome. The occurrence of gonadal mosaicism increases the recurrence risk significantly and is often either underestimated or not even taken into account in genetic counseling where new mutation is suspected.

Frontonasal dysplasia, callosal agenesis, basal encephalocele, and eye anomalies syndrome with a partial 21q22.3 deletion

We describe a girl with a phenotype characterized by frontonasal dysplasia, callosal agenesis, basal encephalocele, and eye anomalies who presents a 46,XX,r(21) karyotype. Array-comparative genomic hybridization using the Afflymetrix 100K DNA oligoarray set showed an interstitial deletion 21q22.3 of approximately 219 kb. Conventional karyotype of both parents was normal, and it was not possible to perform the molecular studies. In this report we raise the hypothesis that the deleted genes located at 21q22.3 could account to the phenotype.

Neural Crest Cell Survival Is Dependent on Rho Kinase and Is Required for Development of the Mid Face in Mouse Embryos

Neural crest cells (NCC) give rise to much of the tissue that forms the vertebrate head and face, including cartilage and bone, cranial ganglia and teeth. In this study we show that conditional expression of a dominant-negative (DN) form of Rho kinase (Rock) in mouse NCC results in severe hypoplasia of the frontonasal processes and first pharyngeal arch, ultimately resulting in reduction of the maxilla and nasal bones and severe craniofacial clefting affecting the nose, palate and lip. These defects resemble frontonasal dysplasia in humans. Disruption of the actin cytoskeleton, which leads to abnormalities in cell-matrix attachment, is seen in the RockDN;Wnt1-cre mutant embryos. This leads to elevated cell death, resulting in NCC deficiency and hypoplastic NCC-derived craniofacial structures. Rock is thus essential for survival of NCC that form the craniofacial region. We propose that reduced NCC numbers in the frontonasal processes and first pharyngeal arch, resulting from exacerbated cell death, may be the common mechanism underlying frontonasal dysplasia.

Six3 expression is augmented in the facial primordia of mice with misexpression of six2 associated with frontonasal dysplasia

We have previously described the Br mutant mouse displaying heritable frontonasal dysplasia. Linkage analysis mapped the mutation near the homeobox transcription factor six2, normally expressed in the facial mesenchyme during development. The purpose of this study is to determine expression patterns of six2, as well as possible upstream and downstream targets of six2, in the developing midface. The three sets of facial prominences (medial, lateral, and maxillary) of E11.5 embryos were dissected and RNA extracted for qPCR assays and microarray analysis. Medial nasal prominences (MNP) were also taken for cell culture. qPCR results indicated six2 expression is highest in the MNP and demonstrated haploinsufficient down‐regulation in each of the three facial prominence sets in the Br mouse. Microarray results suggested the misregulation of several genes in the Br midface, including another member of the Six family of transcription factors: six3. qPCR and immunohistochemistry for six3 substantiated its upregulation in the microarray. Future work using RNA interference on six2 will be used to investigate possible pathways involving six2 and six3. Preliminary results using an in vitro knockdown of six2, performed on an MNP cell culture system utilizing siRNA, demonstrated a 65% knockdown of six2. These results may enable further in vitro work in order to elucidate a pathway in the developing midface involving six2.Grant Funding Source : NIH R01DK064752 (SL) &amp; NCRR 5P20RR024206 (SJS)

Esrp1 and Esrp2 expression in the developing midface and kidney of mice with frontonasal dysplasia and renal hypoplasia

The Brachyrrhine (Br) mutant mouse displays heritable frontonasal dysplasia (FND) and renal hypoplasia (RH). Previous DNA microarray analysis on embryonic Br facial explants showed a misexpression of several genes, two of which are Esrp1 and Esrp2. Together, the Esrp genes play an essential role in the regulation of epithelial‐mesenchymal transition—an important process in craniofacial and kidney development. The primary objective of this study is to determine if Esrp1 and ‐2 contributes to a developmental pathway leading to FND or RH in the Br mouse and, specifically, if there is a difference in Esrp1 and ‐2 expression in the developing midface and kidneys of wild type (WT) and Br adults and embryos. WT and Br/Br E11.5 medial nasal prominences (MNP) and E15.5 and E18.5 kidneys were dissected and RNA extracted for qPCR expression analysis. Preliminary results show minimal difference in Esrp1 and ‐2 expression in MNPs of WT and Br embryos, and an increase in Esrp2 expression from E15.5 to E18.5 WT kidneys. Future work involving qPCR and immunohistochemistry will be completed to better understand the expression patterns of these two genes. Results from this study will contribute to our understanding of the genetic basis of craniofacial and kidney morphogenesis.Grant Funding Source: 1R01‐DK‐064752 (SL)

Craniofacial features resembling frontonasal dysplasia with a tubulonodular interhemispheric lipoma in the adult 3H1 tuft mouse

Intracranial lipomas are rare, but 45% of them occur along the midline cisterns between the hemispheres and are often associated with corpus callosum hypoplasia and craniofacial defects. They are difficult to detect as they are generally asymptomatic and visible by MRI or by postmortem examination. The exact cause of these interhemispheric lipomas is not known, but they arise from a developmental defect resulting in the maldifferentiation of mesenchymal cells into mesodermal derivatives that are not normally present. We have identified a new mouse mutant called tuft, exhibiting a forebrain, intracranial lipoma with midline craniofacial defects resembling frontonasal dysplasia (FND) that arose spontaneously in our wild-type 3H1 colony. The tuft trait seems to be transmitted in recessive fashion, but approximately 80% less frequent than the expected Mendelian 25%, due to either incomplete penetrance or prenatal lethality. MRI and histologic analysis revealed that the intracranial lipoma occurred between the hemispheres and often protruded through the sagittal suture. We also observed a lesion at the lamina terminalis (LT) that may indicate improper closure of the anterior neuropore. We have mapped the tuft trait to within an 18 cM region on mouse chromosome 10 by microsatellite linkage analysis and identified several candidate genes involved with craniofacial development and cellular differentiation of adipose tissue. Tuft is the only known mouse model for midline craniofacial defects with an intracranial lipoma. Identifying the gene(s) and mutation(s) causing this early developmental defect will help us understand the pathogenesis of FND and related craniofacial disorders.

A Novel de Novo Mutation Within EFNB1 Gene in a Young Girl with Craniofrontonasal Syndrome

Craniofrontonasal syndrome is mainly characterized by frontonasal dysplasia, telorbitism, a broad nasal root, and frequently a bifid nose and coronal craniosynostosis. Craniofrontonasal syndrome is an X-linked disorder with an unusual pattern of inheritance because heterozygous females are more severely affected than hemizygous males. The craniofrontonasal syndrome-causing gene is EFNB1, localized in the border region of chromosome Xq12 and Xq13.1, encoding for protein ephrin-B1. Here we aim to investigate the underlying genetic defect of a young girl with craniofrontonasal syndrome. The patient underwent surgical correction of her craniofacial deformities. Genetic analysis was carried out by polymerase chain reaction. Products of exon 2 of the EFNB1 gene were sequenced as well as digested with BpmI enzyme. A novel de novo missense mutation 373G>A was identified within the EFNB1 gene, leading to the replacement of glutamic acid at amino acid position 125 with lysine. The replacement of Glu125 with Lys, which lies within the G-H loop, part of the dimerization ligand-receptor interface, is expected to disrupt the interaction between the Eph receptor and ephrin B1 ligand, thus leading to craniofrontonasal syndrome.

Frontonasal dysplasia (Median cleft face syndrome)

This is a report of a rare case of frontonasal dysplasia (FND) in a full-term girl with birth weight of 2.750 kg. The baby had the classical features of FND. There were no other associated anomalies. There was no history of consanguinity and no family history of similar conditions. So inheritance of this case could be considered sporadic. Maxillofacial surgery should be considered for all patients for whom improvement is possible. However, in developing countries where there are considerable limitations in provision of social services, with economic and educational constraints, correction of such major defects remains a challenging task.

Frontal Congenital Lipoma

Frontonasal dysplasia (FND) is a rare syndrome characterized by malformations of the central portion of the face, especially of the forehead, nose, and philtrum. FND is associated with hypertelorism, a hidden encephalocele, and a cleft of the nose. Occasionally, affected individuals also experience abnormalities of the brain and craniofacial bones. In such cases, a frontal lipoma or calcification of the falx cerebri suggest the existence of a lipoma of the corpus callosum. We present the case of a male newborn with a congenital lipoma 15 mm in size located in the medial frontal line. Magnetic resonance imaging confirmed complete agenesis of the corpus callosum. While there is controversy about the association of frontal lipoma and lipoma of the corpus callosum and FND, we believe our case supports the concept that the changes are due to the same underlying pathogenic mechanism. Therefore, we recommend imaging of the central nervous system in newborns with a congenital lipoma located in the craniofacial midline.

Higher incidence of thyroid agenesis in Mexican newborns with congenital hypothyroidism associated with birth defects

BackgroundCongenital hypothyroidism (CH) is the most common endocrine system disorder in newborns. Ectopic thyroid and agenesis are the most frequent thyroid structural malformations. Several reports have shown that CH is associated with birth defects (BD) ranging from congenital heart disease to ocular and gastrointestinal anomalies. AimsWe investigated how many and what types of BD were associated with CH in Mexican children. Study designCross-sectional study conducted in patients with confirmed CH. SettingHighly specialized government pediatric center in Mexico City. SubjectsWe included 212 patients with permanent CH identified by newborn screening. ResultsWe found that 24% of patients with CH also had BD, and that there was a higher prevalence of thyroid agenesis in the group of patients with CH associated with BD (CH+BD) versus the isolated CH group (p=0.007). There were more females than males in both groups. The most common BD were congenital heart diseases, especially those of the atrial septum, followed by patent ductus arteriosus, found as a single malformation or as part of a complex congenital heart disease. In this study, we found Hirschsprung disease, Beckwith–Wiedemann syndrome, Pierre Robin sequence, Albright's osteodystrophy, VATER association, and frontonasal dysplasia associated with CH. ConclusionsIn this study population, there was a high prevalence of BD in patients with permanent CH. Thyroid agenesis was the main etiological cause of CH in patients with associated congenital malformations. The high prevalence of CH+BD underlines the need for a comprehensive clinical diagnostic approach of the patients with CH.

Frontonasal dysplasia; phenotypic spectrum of related malformation syndromes and their molecular basis

Frontonasal dysplasia; phenotypic spectrum of related malformation syndromes and their molecular basis