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Oculoauriculofrontonasal Dysplasia Syndrome With Additional Clinical Features
Abstract
Oculo-auriculo-vertebral spectrum and frontonasal dysplasia are two well-known examples of dysmorphology syndromes. Oculoauriculofrontonasal syndrome (OAFNS) is a clinical entity involving the characteristics of both OAVS and FND and is thought to be a result of the abnormal development of structures in the first and the second branchial arches, including the abnormal morphogenesis of maxillary processes. Herein we report a case of OAFNS with cliteral hypertrophy, premaxillary teeth, and inguinal hernia, features not previously reported in the literature.
... The term "oculoauriculofrontonasal" was coined by Carey and Yong (1981) to describe the combination of clinical findings. Synonyms include ophthalmofrontonasal dysplasia, Golabi-Gonzales-Edwards syndrome, hemifacial microsomia type III-frontonasal type, and oculoauriculofrontonasal dysplasia (Casey et al., 1996;Golabi et al., 1983;Tenconi & Hall, 1983;Tunc et al., 2017). ...
... The literature review resulted in 82 individuals from 45 articles presenting overlapping features of OAVS and FND. Sixty-five individuals from 33 articles presenting clinical findings compatible with the diagnosis or reported as OAFNS were considered (Adolphs et al., 2012;Al-Gazali et al., 1996;Bartolozzi et al., 1984;Borumandi et al., 2015;Carey & Yong, 1981;Casey et al., 1996;Castillo et al., 1983;Evans et al., 2013;Fleischer-Peters, 1969;Fontaine et al., 1983;Gabbett et al., 2008;Gawrych et al., 2014;Golabi et al., 1983;Gupta et al., 1968;Gustavson & Chen, 1985;Ishmael et al., 2002;Ito et al., 2019;Johnson et al., 2005;Joos & Anastassov, 1998;Kennedy et al., 1998;Lehalle et al., 2018;Musarella & Young, 1986;Naidich et al., 1988;Román Corona-Rivera et al., 2007;Rosenstein, 1971;Sedano & Gorlin, 1988;Sitzmann & Schuch, 1965;Tanna et al., 2012;Tarateta et al., 1978;Tenconi & Hall, 1983;Tillman, 1967;Toriello et al., 1995;Tunc et al., 2017). ...
... In most instances, the orofacial cleft was associated with one or more rare craniofacial clefts. Among rare craniofacial clefts, considering both soft and bone tissue, the median cleft (Tessier number 0) was the most frequent, present in 72% of (Adolphs et al., 2012;Al-Gazali et al., 1996;Bartolozzi et al., 1984;Borumandi et al., 2015;Carey & Yong, 1981;Casey et al., 1996;Castillo et al., 1983;Evans et al., 2013;Fleischer-Peters, 1969;Fontaine et al., 1983;Gabbett et al., 2008;Gawrych et al., 2014;Golabi et al., 1983;Gupta et al., 1968;Gustavson & Chen, 1985;Ishmael et al., 2002;Ito et al., 2019;Johnson et al., 2005;Joos & Anastassov, 1998;Kennedy et al., 1998;Lehalle et al., 2018;Musarella & Young, 1986;Naidich et al., 1988;Román Corona-Rivera et al., 2007;Rosenstein, 1971;Sedano & Gorlin, 1988;Sitzmann & Schuch, 1965;Tanna et al., 2012;Tarateta et al., 1978;Tenconi & Hall, 1983;Tillman, 1967;Toriello et al., 1995;Tunc et al., 2017). c Median cleft not included. ...
The oculoauriculofrontonasal syndrome (OAFNS) is a rare condition, with unknown etiology, characterized by the association of frontonasal dysplasia (FND) and oculoauriculovertebral spectrum (OAVS). Main clinical findings include widely spaced eyes, epibulbar dermoid, broad nose, mandibular hypoplasia, and preauricular tags. Here, we describe a case series of 32 Brazilian individuals with OAFNS and review the literature ascertaining individuals presenting phenotypes compatible with the diagnosis of OAFNS, aiming to refine the phenotype. This series emphasizes the phenotypic variability of the OAFNS and highlights the occurrence of rare craniofacial clefts as a part of the phenotype. The ectopic nasal bone, a hallmark of OAFNS, was frequent in our series, reinforcing the clinical diagnosis. The absence of recurrence, consanguinity, chromosomal, and genetic abnormalities reinforces the hypothesis of a nontraditional inheritance model. The phenotypic refinement provided by this series contributes to an investigation regarding the etiology of OAFNS.
... The craniofacial tissues derive from the cranial neural crest cells, a population of pluripotent cells that arise from the dorsal aspect of the neural tube and migrate to populate the frontonasal process and the first, second, third, and fourth pharyngeal arches (Le Lievre & Le Douarin, 1975). About 40 individuals with OAFNS have been described in the literature (Adolphs et al., 2012;Casey, Braddock, Haskins, Carey, & Morales, 1996;Evans et al., 2013;Gabbett et al., 2008;Gawrych, Janiszewska-Olszowska, & Chojnacka, 2014;Golabi, Gonzalez, & Edwards, 1983;Gupta et al., 1968;Ishmael, Begleiter, Regier, & Butler, 2002;Johnson, Benoit, Pierre-Louis, Keating, & Chitayat, 2005;Musarella & Young, 1986;Roman Corona-Rivera et al., 2007;Toriello, Higgins, & Mann, 1995;Tunc et al., 2017). Except for two siblings born from a diabetic mother (Golabi et al., 1983), all have a sporadic occurrence. ...
... ). In the series, only one patient had an initial diagnosis of OAFNS; seven individuals (39%) were referred for suspicion of Pai syndrome, nine (50%) for FND, and one fetus for suspicion of either PS or OAVS.All cytogenetic and molecular investigations reported in patients with OAFNS in the literature were negative, including karyotype, array comparative genomic hybridization (CGH)(Adolphs et al., 2012;Guimiot et al., 2009;Tunc et al., 2017), ALX3(Adolphs et al., 2012) andGLI3(Guimiot et al., 2009) sequencing. We performed trio-based ES and GS in three patients and their healthy parents, looking in the first step for de novo variants, as the occurrence of OAFNS is usually sporadic. ...
The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo‐auriculo‐vertebral spectrum (OAVS)‐associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next‐generation sequencing strategy performed on blood‐derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.
... Tunc et al listed 10 symptoms of OAFNS. 15 Our case had 6 of these: microtia, preauricular tags, a notched nasal tip/bifid nose, cleft palate/lip, mandibular hypoplasia, and facial asymmetry. None of the 4 signs related to eyes/nervous system was recorded in our case: epibulbar dermoid, midbrain lipoma, encephalocele, or vertebral defect. ...
Oculo-auriculo-fronto-nasal syndrome (OAFNS) is a rare anomaly characterized by features overlapping those of frontonasal dysplasia (FND) and the oculo-auriculo-vertebral spectrum (OAVS). ¹ The FND features malformation of frontonasal process-derived structures, characterized by anomalies in the central portion of the face. The OAVS is characterized by developmental anomalies of the first and second pharyngeal arches. The OAFNS is a condition with clinical features of both FND and OAVS.
Here, the authors present the case of a male with OAFNS who not only exhibited typical OAFNS symptoms but also a dysplastic bony structure that bridged the anterior nasal spine and inferior nasal bones, and unilateral type 3 Duane retraction syndrome (absence of right-eye abduction). Abnormal nasal bones are characteristic of OAFNS; such abnormalities are absent from FND and OAVS. The authors reduced the dysplastic nasal bony structure via open external rhinoplasty, followed by lateral nasal osteotomy when he was 16 years of age. The nasal dorsum appeared natural after surgery and he was satisfied with the result.
Cleft 1–13 is one of the three interorbital rare clefts. According to Sedano, it belongs to the spectrum of frontonasal dysplasia as the type 3 facies. It has, as a consequence, hypertelorism and nasal anomalies. It runs from the nasal aperture toward the paramedian frontal area and the ethmoidal shelf on the skull base, where it can give way to an encephalocele. In its unilateral form, it is asymmetric, but when bilateral, it becomes symmetric, confusing, and easily misdiagnosed as a cleft 0–14. For the study, we reviewed 50 patients and the data of 156 cases reported in the literature.
Its path is identical to the cleft 2–12. The difference is between a clefting phenotype for cleft 1 versus a hypoplastic phenotype for cleft 2. Cleft 1 is called nasoschisis since it is an accurate paramedian nasal cleft. Mutations responsible for typic cleft 1–13 phenotype have been reported mainly on ALX1, 3, and 4.
Objectives
Congenital frontonasal dysplasia (CFND) is a rare heterogeneous collection of facial deformities. Due to the range of complexity, surgical management is not standardized.
Methods
We present a severe case of CFND and approach to managing multiple defects with a focus on rhinoplasty.
Results
This infant was born full term with a large mass instead of a nose, a bilateral cleft lip and palate, and hypertelorbitism. Our primary concerns initially were to address communication with the intracranial cavity, preserve a nasal lining, and improve nasal appearance and airway function in the short term without interfering with subsequent rhinoplasty and adult nasal appearance.
Conclusions
This complex case of CFND is more severe than anything we encountered in our literature review and demonstrates the necessity for multidisciplinary approach to multiple craniofacial defects. Future plans for this patient include rhinoplasty with auricular graft, scar revision, and addressing tip support.
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.
Frontonasal malformation (FNM) is a developmental field defect representing abnormal morphogenesis of the frontonasal eminence. The oculoauriculovertebral spectrum (OAVS) has been used to describe a broader range of first and second branchial-arch defects including hemifacial microsomia and Goldenhar's syndrome. A combination of FNM and OAVS has been described in the literature in 13 cases. This condition has been labeled as the oculoauriculofrontonasal syndrome, as well as ophthalmofrontonasal dysplasia. We have evaluated four patients with both FNM and OAVS. The pattern of malformation involves only the craniofacies: they have no vertebral defects, heart disease, or encephaloceles. The categorization of these four individuals and those in the literature raises interesting issues regarding syndrome classification. Originally, it was suggested that perhaps this disorder was a variation of Goldenhar's syndrome. However, now that it has become evident that FNM and OAVS are malformation patterns of etiologic and presumably pathogenetic heterogeneity, a more likely hypothesis is that when these two defects occur together, this represents a unique syndrome pattern. The purpose of this article is to suggest that the combination of OAVS and FNM may be a distinct entity, representing a discreet subset of patients.
We report a male with features of frontonasal dysplasia, but also with ocular and auricular defects. This child most likely has oculoauriculofrontonasal syndrome, an autosomal recessive syndrome first described in 1981. We also review the literature on this syndrome, and discuss differential diagnosis.
In mice, a lack of cryptochrome results in up-regulation of aldosterone production due to high expression of the 3β-hydroxysteroid dehydrogenases (HSD3β) gene. The HSD3β pathway might play a pivotal role in aldosterone synthesis. This study aimed to determine the association of HSD3β and HSD3β2 gene variations with primary aldosteronism in a Taiwanese population.
In this case-control cohort, 688 consecutive ethnically matched unrelated individuals including 362 primary aldosteronism and 326 essential hypertension cases were recruited. Nineteen tag single-nucleotide polymorphisms (SNPs) across HSD3β1, HSD3β2, and CYP11β2 were genotyped. Expression of HSD3β mRNA and immunohistochemical stain of HSD3β in the specimens of aldosterone-producing adenoma (APA) was compared with that in nonfunctional incidentaloma.
The SNPs of rs12410453 A allele in HSD3β2 gene [odds ratio (OR) 1.92, 95% confidence interval (CI) 1.13-3.32, P=0.018] and rs6203 C allele in the HSD3β1 gene (OR 2.21, 95% CI 1.28-3.95, P=0.006) showed significant association with primary aldosteronism, with corresponding population attributable risk of 6.7 and 30.7%, respectively. Primary aldosteronism patients of non-CC in rs6203 and non-GA in rs12401453 had lower plasma aldosterone-to-renin ratio. A haplotype in a linkage disequilibrium block containing rs6203 associated significantly with serum potassium level (OR 1.24, 95% CI 1.02-1.24, P=0.026). The expressions of HSD3β1 mRNA, HSD3β2 mRNA and HSD3β protein were increased in APA, as compared to incidentaloma.
Risk-conferring genetic variations in the HSD3β gene influenced susceptibility of primary aldosteronism. Concomitant presence of rs6203 CC and rs12410453 GA genotypes synergistically increased aldosterone-to-renin ratio.
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. © 2013 Wiley Periodicals, Inc.
Craniofacial clefts are certainly among the most challenging congenital malformations with respect to functional, aesthetic and psychosocial consequences. The aetiology is still under discussion, recent molecular genetic findings suggest defects in the ciliary function of neural crest cells during facial development. The severity of craniofacial clefting is known to be extremely variable. Different classifications have been proposed however nomenclature is not uniform. If vertical, median craniofacial clefting of fronto-naso-maxillary structures is accompanied by auriculo-mandibular malformations the term oculo-auriculo-fronto-nasal syndrome (OAFNS) has been proposed. Extreme craniofacial abnormalities have to be expected in this rare disorder. Adequate correction is a surgical challenge and interventions have to be adapted individually to patient's needs with respect to general condition, age and growth. This case report describes both the underlying pathology as well as the interdisciplinary management of a female patient from birth to 6years of age affected by this rare combination of vertical craniofacial clefting and bilateral auriculo-mandibular dysplasia.
We describe a recessively inherited frontonasal malformation characterized by a distinctive facial appearance, with hypertelorism, wide nasal bridge, short nasal ridge, bifid nasal tip, broad columella, widely separated slit-like nares, long philtrum with prominent bilateral swellings, and midline notch in the upper lip and alveolus. Additional recurrent features present in a minority of individuals have been upper eyelid ptosis and midline dermoid cysts of craniofacial structures. Assuming recessive inheritance, we mapped the locus in three families to chromosome 1 and identified mutations in ALX3, which is located at band 1p13.3 and encodes the aristaless-related ALX homeobox 3 transcription factor. In total, we identified seven different homozygous pathogenic mutations in seven families. These mutations comprise missense substitutions at critical positions within the conserved homeodomain as well as nonsense, frameshift, and splice-site mutations, all predicting severe or complete loss of function. Our findings contrast with previous studies of the orthologous murine gene, which showed no phenotype in Alx3(-/-) homozygotes, apparently as a result of functional redundancy with the paralogous Alx4 gene. We conclude that ALX3 is essential for normal facial development in humans and that deficiency causes a clinically recognizable phenotype, which we term frontorhiny.
A comprehensive review and critical analysis of oculoauriculovertebral spectrum are provided. Topics discussed include nosologic problems, epidemiology, etiology (chromosomal, monogenic, teratogenic), and pathogenesis (hematoma formation, other vascular mechanisms, overripeness ovopathy). Clinical manifestations are thoroughly reviewed, updated, and documented for craniofacial features, central nervous system characteristics (including the wide spectrum of CNS malformations that make up the so-called "expanded Goldenhar complex"), congenital heart defects, and various other anomalies (kidney, lung, gastrointestinal tract). A number of conditions are discussed that are commonly differentiated from oculoauriculovertebral spectrum but have overlapping relationships, in some instances, with frontonasal dysplasia, branchio-oto-renal (BOR) syndrome, Townes-Brocks syndrome, Wildervanck syndrome, DiGeorge sequence, and several associations (VATER, CHARGE, and MURCS).
Here we describe the phenotypic characteristics of a single craniofacial clinic population of 294 individuals affected with Oculoauriculovertebral dysplasia (OAV) and variants. To our knowledge, this is the largest population so described in the literature.
The study population was divided into five subgroups based on the presence of combinations of minimal diagnostic criteria: microtia, mandibular hypoplasia, anomalies of the cervical spine and/or epibulbar or lipodermoids. The following data were recorded: (1) sex (M:F 191:103); (2) race (78% Caucasian); (3) the presence of unilateral or bilateral microtia (193 unilateral, 98 bilateral); (4) the presence of symmetric microtia in bilateral cases (34/98); (5) the presence of mandibular hypoplasia ipsilateral or contralateral to the microtic ear or most severely microtic ear in bilateral cases (135/137 were ipsilateral in unilateral cases, 55/62 were ipsilateral in bilateral cases); (6) the number of individuals with no Other congenital anomaly in addition to the minimal diagnostic criteria (154/294), with only one other congenital anomaly (51/294), and with two or more other congenital anomalies (89/294); and 7) the type of other congenital anomalies. Finally, we compared our results with other studies.
Findings from our study include: (1) mandibular asymmetry should be expected in patients with unilateral or bilateral microtial; (2) bilateral involvement is frequent in patients with microtia; (3) other malformations are seen frequently in all subgroups; (4) anomalies of the cervical spine are more likely to be associated with other anomalies; and (5) other malformations are seen in all systems and should be searched for to provide optimal management.
We report on a child with severe midline facial cleft, bilateral cleft lip and palate, telecanthus, S-shaped palpebral fissures, limbic dermoid, midface hypoplasia, hypoplastic corpus callosum, and multiple skin appendages. This case may be an example of severe frontofacionasal "dysplasia" or a newly recognised syndrome.
Frontonasal malformation (FNM) is a developmental field defect representing abnormal morphogenesis of the frontonasal eminence. The oculoauriculovertebral spectrum (OAVS) has been used to describe a broader range of first and second branchial-arch defects including hemifacial microsomia and Goldenhar's syndrome. A combination of FNM and OAVS has been described in the literature in 13 cases. This condition has been labeled as the oculoauriculofrontonasal syndrome, as well as ophthalmofrontonasal dysplasia. We have evaluated four patients with both FNM and OAVS. The pattern of malformation involves only the craniofacies: they have no vertebral defects, heart disease, or encephaloceles. The categorization of these four individuals and those in the literature raises interesting issues regarding syndrome classification. Originally, it was suggested that perhaps this disorder was a variation of Goldenhar's syndrome. However, now that it has become evident that FNM and OAVS are malformation patterns of etiologic and presumably pathogenetic heterogeneity, a more likely hypothesis is that when these two defects occur together, this represents a unique syndrome pattern. The purpose of this article is to suggest that the combination of OAVS and FNM may be a distinct entity, representing a discreet subset of patients.
We report an adult male patient born to normal and non-consanguineous parents with midline craniofacial defects associated with branchial arch anomalies. This combination of signs belongs to the oculoauriculofrontonasal spectrum. We compare our case with those previously reported who had similar findings and discuss clinical aspects of the oculoauriculofrontonasal spectrum and frontofacionasal dysplasia.
We report a nine-month-old Caucasian male with features seen in oculoauriculovertebral spectrum (OAVS) and frontonasal dysplasia sequence (FND) born to normal, non-consanguineous parents and review the literature. His malformations included a left pre-auricular skin tag, severely hypoplastic right pinna without an external canal, severely everted and hypoplastic left upper eyelid, bilateral cleft lip and palate, bifid broad nasal tip, ocular hypertelorism, micrognathia, hypoplastic mandible, an extra cervical rib on the left, hemivertebrae at T3-4, agenesis of the posterior corpus callosum with a midline lipoma, and an extra renal pelvis. This constellation of anomalies is consistent with the diagnosis of oculoauriculofrontonasal syndrome (OAFNS) which appears to be a distinct condition from either OAVS or FND but with overlapping features.
Here we report on a girl presenting with midline cleft lip/palate, prominent forehead, macrocephaly, first branchial arch anomalies, and tetralogy of Fallot. Imaging studies showed polymicrogyria, enlarged ventricles with a large cystic lesion extending postero-superiorly over the cerebellum, abnormally modeled cerebellum, and congenital aqueductal stenosis. To our knowledge, this combination of clinical signs involving the frontonasal process, midline lip clefting, congenital heart malformation, and severe CNS developmental abnormalities has not previously been reported. Clinical, imaging data, as well as differential diagnosis are discussed.
We report four patients with GLI2 mutations together with their associated phenotypes: (1) holoprosencephaly-like phenotype, (2) anophthalmia, branchial arch anomalies, and CNS abnormalities, (3) heminasal aplasia and orbital anomalies, and (4) lobar holoprosencephaly. This diversity of phenotypes expands our understanding. Findings include not only (1) holoprosencephaly or a holoprosencephaly-like phenotype, but also (2) heminasal aplasia with orbital anomalies, and (3) branchial arch anomalies of the type seen in hemifacial microsomia with anophthalmia and in oculoauriculofrontonasal syndrome. Finally, this is the first report of a double mutation involving GLI2 and PTCH in the same patient.
Human dysmorphology syndromes are frequently defined by characteristic abnormalities in facial morphogenesis. Two such well recognized syndromes are the oculoauriculovertebral spectrum (OAVS) and frontonasal dysplasia (FND). OAVS is diagnosed on the basis of the presence of typical facial features which can include microtia, preauricular tags, hemifacial microsomia, lateral face clefting, epibulbar dermoids, and upper palpebral colobomata. FND is characterized by ocular hypertelorism, nasal clefting, and anterior cranium bifidum occultum. After the first patient was described with features of both OAVS and FND, at least a further 25 patients presenting the 'oculoauriculofrontonasal syndrome' (OAFNS) have been reported. We report on four more patients with OAFNS and review their features, together with those of the other patients reported in the medical literature. We suggest that, statistically, OAFNS is more likely to be a sporadically occurring condition rather than an inherited autosomal recessive trait, as previously suggested. We cannot, however, definitively exclude the possibility of autosomal dominant transmission. Considering the question of whether OAFNS is a part of OAVS, FND, or a distinct clinical entity, we conclude that, for the time being, OAFNS should be considered to be a distinct syndrome, to further our understanding of the aetiology of these conditions.