Craniosynostosis is a common neonatal condition and has been linked to a multitude of skeletal and systemic abnormalities.1,2 Craniosynostosis has been demonstrated to be caused by variants in fibro-blast growth factor receptor (FGFR) genes TWIST1, TCF12, and ERF. Of the common FGFR-related craniosynostosis syndromes, a diagnosis of Apert, Pfeiffer, and Crouzon syndromes is based on clinical findings. The most common cause of syndromic craniosnyostosis is Crouzon syndrome; it is seen in approximately 16 per 1 million newborns.3 Crouzon syndrome is an autosomal dominant condition predominantly caused by mutations in FGFR2. FGFR2 is expressed in the periosteum, optic nerve sheath, and extraocular muscle.4 Mutations in the FGFR2 gene are thought to lead to overstimulation of signalling by the FGFR2 protein, which causes the bones of the skull to fuse prematurely. The phenotypic presentation of Crouzon syndrome can vary widely, but common features include hypertelorism, exophthalmos and external strabismus, beaked nose, short upper lip, hypoplastic maxillae, and a relative mandibular prognathism.5 Other ophthalmological manifestations include myopia, globe subluxation, coloboma, extraocular muscle hypoplasia, and development and progression of optic atrophy.6 In contrast to differential diagnoses for craniosynostosis, Crouzon syndrome is usually associated with normal hands, feet, and intelligence.
Optic nerve hypoplasia is a congenital abnormality characterized by an underdevelopment of the optic nerves, diagnosed by the appearance of smaller than expected optic discs on direct funduscopy. It is an important diagnosis because it is frequently associated with endocrine, neurological, and other ocular defects.7 It is more commonly seen bilaterally than unilaterally, and the associated visual impairment is non-progressive in nature.
The reported incidence of optic nerve hypoplasia varies widely from study to study, and is estimated to be present in 1 in 2,287 to 1 in 10,000 live births.8,9 The incidence is increasing, due to an increase in either the number of cases or in detection through ophthalmological surveillance programs and advanced imaging techniques.10 It is the most common cause of congenital blindness worldwide. In schools for visually impaired children, it is responsible for 5.7% to 12.9% of cases11–14 and it is the cause of visual impairment in 27% of the legally blind children in Ireland.15 It has been associated with young maternal age, low maternal weight, primiparity, fetal alcohol syndrome, maternal diabetes mellitus, prematurity, antepartum bleeding, and twin-to-twin transfusion syndrome.9,16–22 Links with illicit drug use and fertility treatments remain uncertain.18
The diagnosis is made by an ophthalmologic examination with funduscopy. Neuroimaging in optic nerve hypoplasia is predominantly used to assess for associated brain malformations (eg, hypoplasia of the corpus callosum, absent septum pellucidum, or pituitary malformations) that can be related to the diagnosis. Optic nerve hypoplasia is usually managed with early treatment of strabismus, refractive errors, and amblyopia, and a 22% rate of significant visual impairment has been reported.7
Syndromic associations with optic nerve hypoplasia have been described in the literature. Septo-optic dysplasia is commonly associated with optic nerve hypoplasia.23 CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retardation of growth, Genitourinary malformations, and Ear abnormalities) syndrome has an 8% incidence of optic nerve hypoplasia, although other ocular issues are more common.24 Approximately 30% of patients with frontonasal dysplasia have optic nerve hypoplasia,25 and it is the most common ocular abnormality in fetal alcohol syndrome, with an incidence of 48%.16,17,19
There have been three other reports of cases of optic nerve hypoplasia and craniosynostosis in the literature to date. Tiwari et al.26 described a 20-year-old woman with Apert syndrome, optic nerve hypoplasia, and septum pellucidum agenesis. A separate genetic mutation for septo-optic dysplasia and optic nerve hypoplasia was not identified. Wakeling et al.27 described a 4-year-old girl with sagittal craniosynostosis, subglottic stenosis, dental anomalies, and optic nerve hypoplasia with septo-optic dysplasia. Zollino et al.28 reported a case series of children with Koolen– de Vries syndrome, one of whom had craniosynostosis and optic nerve hypoplasia. There have been no previous reports of an association between Crouzon syndrome and optic nerve hypoplasia.
A male infant was transferred to our tertiary center after developing respiratory distress during his first feed at 2 hours of age for treatment of suspected choanal atresia. His background was significant for an ovum donor in vitro fertilization pregnancy. His mother was 38 years of age with a history of polycystic ovarian syndrome and epilepsy, but she was not taking medication during the pregnancy. The ultrasound performed at 21 weeks was normal.
He was born in a tertiary maternity unit at 41 weeks' gestation by an emergency caesarean section for fetal bradycardia. Meconium stained liquor was present at delivery. His birth weight was 3.87 kg (25th to 50th percentile) and his occipital-frontal circumference was 35 cm (50th percentile). The Apgar scores were 7 at 1 minute and 9 at 5 minutes. At 2 hours of age, he had a cyanotic episode during his first breastfeeding attempt. He was then transferred to a neonatal intensive care unit, where a nasogastric tube could not be passed beyond the nasal cavity. He was noted to have dysmorphic features, including a high arched palate, bulbous nose, wide nostrils, and downward slanting eyes.
A grade 1 systolic murmur was heard. A computed tomography (CT) scan of the facial bones showed mid face hypoplasia and a membranous stenosis of the choanae bilaterally. An echocardiogram revealed no underlying structural or functional cardiac disease. An ophthalmic review was performed on day 10 of life and again at 6 months of age, and significant bilateral optic nerve hypoplasia was confirmed by direct funduscopy. He had frequent desaturations and increased work of breathing on non-invasive ventilatory support, and underwent dilatation of the choanae under anesthesia on day 5 of life. He required nasal stenting on day 23 of life and again on day 52 of life.
During his admission, cranial asymmetry became apparent and a left unicoronal craniosynostosis was suspected. At 6 weeks old, his occipital-frontal circumference was in the 99th percentile. Magnetic resonance imaging was performed at 2 months of age and showed dilated lateral ventricles and a small optic chiasm (Figure 1). A three-dimensional CT scan of his skull and facial bones was performed at 5 months of age and the patient was subsequently diagnosed as having multiple suture synostoses (Figure 2). The anterior fontanelle was patent, and the coronal suture was patent inferiorly but otherwise fused bilaterally with brachycephaly. The squamoparietal sutures were almost completely fused bilaterally, the sagittal suture was partly fused, and the lambdoid sutures remained unfused. The CT scan confirmed severe mid face hypoplasia and showed increased craniolacunae throughout the calvarium, which were most prominent in the parietal and temporal bones.
Coronal T2 magnetic resonance imaging showing dilated lateral ventricles (black arrow) and small optic chasm (white arrow).
Computed tomography three-dimensional skull and facial bones demonstrating increased craniolacunae throughout the cavarium, multiple suture synostosis, and severe mid face hypoplasia.
Array comparative genomic hybridization analysis of DNA derived from an EDTA peripheral blood sample was performed using an oligonucleotide array with approximately 60,000 probes across the genome at 300 kb gain and 100 kb loss resolution. It showed a male chromosome complement. An increase of approximately 573 kb was detected in the long arm of chromosome 19 at band 19q13.43 between base pair coordinates 56,423,953 and 56,997,186. The significance of this finding in relation to the clinical phenotype was unclear. Further investigations into the pathogenicity of this variant were performed by Genetics Laboratories in Churchill Hospital, Oxford. Sequence analysis of FGFR2 exon IIIc (10) was heterozygous (c.1040C > G p.[Ser347cys]). Sequence analysis of FGFR1, exons 7, FGFR2 exon IIIa (8), FGFR2 exon 7 and 10, and TWIST1 exon 1 detected no pathogenic variant. This variant has been reported several times in the literature in association with Crouzon syndrome. P.Ser347 lies within the functionally important third immunoglobulin loop of the extracellular domain, and this substitution is thought to lead to aberrant disulfide bonding and constitutive activation. The above results confirmed a molecular diagnosis of Crouzon syndrome.
The patient was discharged from the neonatal intensive care unit and was well on day 75 of life. He underwent a posterior cranial vault distraction at 9 months of age. The distractors remained in situ for 10 weeks postoperatively. The infant achieved a satisfactory cosmetic result and there were no acute or subacute complications. He is currently awaiting repair of a split columella, which is a complication of nasal stenting in the neonatal period. Further craniofacial surgeries are planned for him during the next 8 to 10 years. He is receiving ongoing craniofacial, developmental pediatrics, ophthalmology, otolaryngology, and genetics follow-up.
The ocular complications of Crouzon syndrome are numerous and largely consequences of increased intracranial pressure (eg, papilledema, corneal exposure keratopathy, subluxation of the globes, and optic atrophy prior to decompressive craniectomy). Visual impairment rates of up to 35% in one eye and 9% for bilateral impairment have been reported and the most commonly reported cause of visual impairment is amblyopia.29 Optic nerve hypoplasia is not an ocular abnormality typically associated with Crouzon syndrome. When present from birth, optic hypoplasia is associated with several endocrinopathies, primarily brain malformations and developmental delay. Rates of developmental delay of up to 70% have been reported, which is in stark contrast to the normal development expected with Crouzon syndrome.30 Although uncommon in Crouzon syndrome, the association with optic nerve hypoplasia changes the initial work-up, parental discussions regarding longer term outcome, and the developmental follow-up plan. Early diagnosis of optic nerve hypoplasia is important to ensure a timely investigation and treatment of preventable complications (eg, pituitary dysfunction), close observation in terms of visual assessment, adequate counselling, and planning in terms of educational requirements and parental expectations of visual acuity and developmental outcome.
This finding has important implications for the initial investigation of children with Crouzon syndrome. Urgent ophthalmological examination in the neonatal period should be highlighted in all infants with suspected Crouzon syndrome or other craniofacial abnormalities to guide further genetic and endocrine investigations. Should more cases of Crouzon syndrome and optic nerve hypoplasia be reported, data regarding neurodevelopmental outcomes should be collected to ascertain whether children with optic nerve hypoplasia and Crouzon syndrome have similarly high rates of intellectual disability to those with optic nerve hypoplasia and other clinical syndromes.
- Wang JC, Nagy L, Demke JC. Syndromic craniosynostosis. Facial Plast Surg Clin North Am. 2016;24:531–543. doi:10.1016/j.fsc.2016.06.008 [CrossRef]
- Panigrahi I. Craniosynostosis genetics: the mystery unfolds. Indian J Hum Genet. 2011;17:48–53. doi:10.4103/0971-6866.86171 [CrossRef]
- Pal US, Gupta C, Chellappa AA. Crouzon syndrome with primary optic nerve atrophy and normal brain functions: a case report. J Oral Biol Craniofac Res. 2012;2:116–118. doi:10.1016/j.jobcr.2012.03.011 [CrossRef]
- Khan SH, Britto JA, Evans RD, Nischal KK. Expression of FGFR-2 and FGFR-3 in the normal human fetal orbit. Br J Ophthalmol. 2005;89:1643–1645. doi:10.1136/bjo.2005.075978 [CrossRef]
- Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, Van Maldergem L. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet. 2000;66:768–777. doi:10.1086/302831 [CrossRef]
- Garcia GA, Tian JJ, Apinyawasisuk S, Kim S, Akil H, Sadun AA. Clues from Crouzon: insights into the potential role of growth factors in the pathogenesis of myelinated retinal nerve fibers. J Curr Ophthalmol. 2016;28: 232–236. doi:10.1016/j.joco.2016.07.008 [CrossRef]
- Teär Fahnehjelm K, Dahl S, Martin L, Ek U. Optic nerve hypoplasia in children and adolescents; prevalence, ocular characteristics and behavioural problems. Acta Ophthalmol. 2014;92:563–570. doi:10.1111/aos.12270 [CrossRef]
- National Organization for Rare Diseases. Optic nerve hypoplasia. https://rarediseases.org/rare-diseases/optic-nerve-hypoplasia. Author. Published 2015.
- Mohney BG, Young RC, Diehl N. Incidence and associated endocrine and neurologic abnormalities of optic nerve hypoplasia. JAMA Ophthalmol. 2013;131:898–902. doi:10.1001/jamaophthalmol.2013.65 [CrossRef]
- Kaur S, Jain S, Sodhi HB, Rastogi A, Kamlesh. Optic nerve hypoplasia. Oman J Ophthalmol. 2013;6:77–82. doi:10.4103/0974-620X.116622 [CrossRef]
- DeCarlo DK, Nowakowski R. Causes of visual impairment among students at the Alabama School for the Blind. J Am Optom Assoc. 1999;70:647–652.
- Mets MB. Childhood blindness and visual loss: an assessment at two institutions including a “new” cause. Trans Am Ophthalmol Soc. 1999;97:653–696.
- Shi Y, Xu Z. An investigation on causes of blindness of children in seven blind schools in East China [article in Chinese]. Zhonghua Yan Ke Za Zhi. 2002;38:747–749.
- Goh YW, Andrew D, McGhee C, Dai S. Clinical and demographic associations with optic nerve hypoplasia in New Zealand. Br J Ophthalmol. 2014;98:1364–1367. doi:10.1136/bjophthalmol-2013-304605 [CrossRef]
- Khan RI, O'Keefe M, Kenny D, Nolan L. Changing pattern of childhood blindness. Ir Med J. 2007;100:458–461.
- Burke JP, O'Keefe M, Bowell R. Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol. 1991;75:236–239. doi:10.1136/bjo.75.4.236 [CrossRef]
- Hellström A, Wiklund LM, Svensson E. The clinical and morphologic spectrum of optic nerve hypoplasia. J AAPOS. 1999;3:212–220. doi:10.1016/S1091-8531(99)70005-4 [CrossRef]
- Tornqvist K, Ericsson A, Källén B. Optic nerve hypoplasia: risk factors and epidemiology. Acta Ophthalmol Scand. 2002;80:300–304. doi:10.1034/j.1600-0420.2002.800313.x [CrossRef]
- Strömland K. Visual impairment and ocular abnormalities in children with fetal alcohol syndrome. Addict Biol. 2004;9:153–157. doi:10.1080/13556210410001717024 [CrossRef]
- Garcia-Filion P, Borchert M. Prenatal determinants of optic nerve hypoplasia: review of suggested correlates and future focus. Surv Ophthalmol. 2013;58:610–619. doi:10.1016/j.survophthal.2013.02.004 [CrossRef]
- Garcia-Filion P, Fink C, Geffner ME, Borchert M. Optic nerve hypoplasia in North America: a re-appraisal of perinatal risk factors. Acta Ophthalmol. 2010;88:527–534. doi:10.1111/j.1755-3768.2008.01450.x [CrossRef]
- Brennan D, Giles S. Ocular involvement in fetal alcohol spectrum disorder: a review. Curr Pharm Des. 2014;20:5377–5387. doi:10.2174/1381612820666140205144114 [CrossRef]
- Arslanian SA, Rothfus WE, Foley TP Jr, Becker DJ. Hormonal, metabolic, and neuroradiologic abnormalities associated with septo-optic dysplasia. Acta Endocrinol (Copenh). 1984;107:282–288. doi:10.1530/acta.0.1070282 [CrossRef]
- Russell-Eggitt IM, Blake KD, Taylor DS, Wyse RK. The eye in the CHARGE association. Br J Ophthalmol. 1990;74:421–426. doi:10.1136/bjo.74.7.421 [CrossRef]
- Roarty JD, Pron GE, Siegel-Bartelt J, Posnick JC, Buncic JR. Ocular manifestations of frontonasal dysplasia. Plast Reconstr Surg. 1994;93:25–30. doi:10.1097/00006534-199401000-00004 [CrossRef]
- Tiwari A, Agrawal A, Pratap A, Lakshmi R, Narad R. Apert syndrome with septum pellucidum agenesis. Singapore Med J. 2007;48:e62–e65.
- Wakeling EL, Dattani MT, Bloch-Zupan A, Winter RM, Holder SE. Septo-optic dysplasia, subglottic stenosis and skeletal abnormalities: a case report. Clin Dysmorphol. 2003;12:105–107. doi:10.1097/00019605-200304000-00006 [CrossRef]
- Zollino M, Marangi G, Ponzi E, et al. Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients. J Med Genet. 2015;52:804–814. doi:10.1136/jmedgenet-2015-103184 [CrossRef]
- Gray TL, Casey T, Selva D, Anderson PJ, David DJ. Ophthalmic sequelae of Crouzon syndrome. Ophthalmology. 2005;112:1129–1134. doi:10.1016/j.ophtha.2004.12.037 [CrossRef]
- Borchert M, Garcia-Filion P. The syndrome of optic nerve hypoplasia. Curr Neurol Neurosci Rep. 2008;8:395–403. doi:10.1007/s11910-008-0061-7 [CrossRef]