From the Department of Ophthalmology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Presented at the Royal Australian and New Zealand College of Ophthalmologists’ New Zealand Branch Meeting, Christchurch, New Zealand, May 18, 2008.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Andrea L. Vincent, MBChB, FRANZCO, Department of Ophthalmology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Noonan syndrome is a congenital disorder characterized by short stature, facial dysmorphia, webbed neck, congenital cardiac malformations, pectus deformities, and cryptorchidism in males.1 Most frequently, the condition results from mutations in exons 3, 8, 9, and 13 of the PTPN11 gene.2 Ophthalmic abnormalities occur in 95% of patients,3 but an association with Duane-like synkinesis has never been described. Duane syndrome is a disorder of ocular motility consisting of retraction of the globe and narrowing of the palpebral fissure in attempted adduction with restriction of abduction, adduction, or both. The underlying pathology is believed to be an absent or hypoplastic abducens nerve, or its nucleus, and aberrant innervation of the lateral rectus muscle by the oculomotor nerve.4 However, the underlying genetic cause of Duane syndrome is unknown.
We report the novel concurrence of Noonan syndrome and a bilateral Duane-like synkinesis in a 9-year-old boy. This case expands the ocular phenotype of Noonan syndrome and may provide insights into the pathogenesis of Duane syndrome.
A 9-year-old boy of Middle Eastern ethnicity was referred for ophthalmological evaluation. At birth he was noted to have features consistent with Noonan syndrome, including bilateral ptosis, epicanthal folds, downward slanting palpebral fissures, high arched palate, low-set posteriorly rotated ears, webbed neck, low posterior hair line, pectus excavatum, widely spaced nipples, pulmonary stenosis, and bilateral cryptorchidism. There was developmental delay; the patient did not walk until 19 months of age and only spoke two to three words until 36 months of age. Chromosomal analysis revealed a normal male karyotype, 46, XY.
Bilateral frontalis slings were performed at the age of 22 months for severe chin-up head posture. No strabismus surgery was performed at the time of the ptosis operation. Because the surgery was performed at an overseas facility, we do not have details regarding the nature of the sling material or the surgical technique employed. The parents were clinically normal and non-consanguineous, and there was no family history of ocular or systemic disease.
On examination, the patient measured 50 inches in height, weighed 60 pounds, and was of normal intelligence. There were signs of bilateral frontalis slings with mild residual congenital ptosis and marked frontalis action. Ocular motility examination revealed globe retraction with narrowing of the palpebral fissure in adduction and mild restriction of abduction in both eyes, which was more marked in left gaze (Figure).
Figure. Bilateral Duane-Like Synkinesis in a Patient with Noonan Syndrome Showing Globe Retraction and Narrowing of the Palpebral Fissure in Adduction with Mild Restriction of Abduction in Both Eyes.
Uncorrected visual acuity measured 20/40 in the right eye and 20/50 in the left eye. Cycloplegic refraction was +3.25 / −0.50 × 180° in the right eye and +2.50 / −0.50 × 180° in the left eye. Best spectacle-corrected visual acuity was 20/40 in both eyes, suggesting a degree of amblyopia. There were no abnormalities of the cornea, lens, or anterior chamber in either eye on slit-lamp examination and both fundi were normal. Keratometry readings (K1/K2) were 41.93/42.88 diopters in the right eye and 42.24/42.78 diopters in the left eye. Axial length by partial coherence laser interferometry was 24.87 and 25.15 mm in the right and left eyes, respectively.
Genomic DNA was PCR-amplified for analysis of exons 3, 8, 9, and 13 of the PTPN11 gene (GeneDx; Gaithersburg, MD). A bi-directional sequence was obtained and compared against the published gene sequence. No disease-associated mutations were identified in these exons, including their flanking splice sites.
To our knowledge, this is the first report of a Duane-like synkinesis in a patient with Noonan syndrome. Because of the equivocal restriction of abduction, we prefer the term Duane-like synkinesis as opposed to Duane syndrome. This case expands the ocular phenotype associated with Noonan syndrome and could highlight a commonality in the pathogenesis of these two congenital malformation complexes. Furthermore, this case may provide insights into the pathogenesis and genetic basis of Duane syndrome.
Duane syndrome belongs to a group of diseases known as the congenital cranial dysinnervation disorders.5 These diseases are characterized by abnormal eye, eyelid, or facial movement and result from aberrant innervation of the ocular or facial musculature, or both.6 The congenital cranial dysinnervation disorders include congenital fibrosis of the extraocular muscles (CFEOM), Möbius syndrome, horizontal gaze palsy, congenital ptosis, and congenital facial nerve palsy.5 This group of disorders has received increasing attention due to the recent elucidation of the genetic basis of several of the individual diseases.6 There are now more than 10 genetic loci and 5 disease genes known to be associated with congenital cranial dysinnervation disorders, including KIF21A in CFEOM1, PHOX2A in CFEOM2, ROBO3 in horizontal gaze palsy with progressive scoliosis, HOXA1 in Bosley–Salih–Alorainy syndrome, and SALL4 in Duane syndrome with radial ray anomalies PHOX2A mutated in CFOEM2, and SALL4 mutated in Duane syndrome with radial ray abnormalities.5 This novel association with Noonan syndrome may suggest additional genetic mechanisms.
Noonan syndrome is a genetic disease with an autosomal dominant transmission pattern, although approximately 50% of cases are the result of de novo mutations.1 Ophthalmic abnormalities occur in 95% of patients, with the most frequent being hypertelorism, downward slanting palpebral fissures, ptosis, strabismus, and refractive error (Table).1,3,7 It has been suggested that a defect in mesodermal development may underlie both the systemic and ocular manifestations.5 The genetic basis for Noonan syndrome is believed to be aberrant activation of the Ras-mitogen-activated protein kinase signaling cascade.1 This pathway has an important role in controlling embryogenesis, cell differentiation, cell proliferation, and cell death. Approximately 50% of patients with Noonan syndrome have mutations in the gene PTPN11 and the majority of these mutations are in exons 3, 8, 9, or 13.2 Although no mutation was identified in any of these exons in our patient, this does not exclude a PTPN11 mutation, nor a mutation in one of the other genes known to cause Noonan syndrome—SOS1, RAF1, or KRAS. Noonan syndrome was essentially a clinical diagnosis until the recent identification of the multiple genetic determinants; therefore, the clinical features and appearance alone are sufficient to confirm the diagnosis.
Table: Ocular Abnormalities in Noonan Syndrome
PTPN11 encodes SHP-2, a member of a subfamily of cytoplasmic protein tyrosine phosphatases that relay signals from activated growth receptors to Ras and other effectors. SHP-2 is widely expressed in embryonic and adult tissues and is essential for several developmental processes, including the development of axial and paraxial mesodermal structures such as the main mass of the eyelids, corneal stroma and endothelium, iris stroma, pupillary membrane, vitreous, retinal circulation, choroid, sclera, extraocular muscles, and the bony orbit.2 SHP-2 is also important in the development of terminal and skeletal structures, as well as cardiac valve development, which accounts for the high incidence of pulmonary valvular stenosis in Noonan syndrome.2 This case may suggest a role for SHP-2 in the development of the oculomotor and abducens nerve and/or their nuclei. Because an association has not been described previously, SHP-2 may not be directly involved in Duane syndrome pathogenesis but may still function within a tightly linked developmental network, which would account for the coexistence of the features. Likewise, the coexistence of Duane syndrome and blepharophimosis–ptosis–epicanthus inversus syndrome is associated with a FOXL2 mutation.8
Although a Duane-like synkinesis has not been previously described in association with Noonan syndrome, strabismus is frequently reported and occurs in up to 48% of patients with Noonan syndrome.3 Furthermore, a wide spectrum of synkinesis is described within families with autosomal dominant Duane syndrome9 and the co-existence of ptosis and abnormal synkinetic eyelid elevation associated with ipsilateral abduction and Duane syndrome occurring within the same family.10 Such familial cases suggest a genetic basis for Duane syndrome and highlight the spectrum of disease that may occur.
Duane syndrome has been frequently reported in association with other congenital malformation syndromes, including Duane-radial ray, Goldenhar, Wildervanck, and Holt–Oram syndromes, and Klippel–Feil anomaly, which may link the disorder to a critical point in embryological development. The majority of ocular and non-ocular structures affected in both Noonan syndrome and Duane syndrome undergo embryological development between 4 and 8 weeks of gestation. The oculomotor and abducens nerve and their nuclei develop between 5 and 8 weeks of gestation.11 This compares with the development of the pinna (6 to 8 weeks’ gestational age), eyelids (4 to 8 weeks’ gestational age), epibulbar dermoids (7 weeks’ gestational age), and the pulmonary valve (which begins to develop at 6 weeks’ gestational age).11 It is therefore plausible that these phenotypic features may result from the pleiotropic effects of a single genetic defect.
Although the observed synkinesis could theoretically result from the previous ptosis surgery, a literature search did not find any association between frontalis slings and synkinesis.
It is unlikely that this association is the result of chance alone. The estimated incidence of Noonan syndrome is between 1:1,000 and 1:2,500 live births,1 whereas Duane syndrome is estimated to occur in 1% to 4% of strabismus cases.10 The prevalence of strabismus in the general population is 4.2%12; thus, the prevalence of Duane syndrome in the general population can be estimated to be between 0.042% and 0.168%. The probability of Noonan syndrome and Duane syndrome occurring in the same patient is therefore between 1:6,000 and 1:60,000. With ongoing genetic research, the nature of this association may be further defined.
- Tartaglia M, Gelb BD. Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2005;6:45–68. doi:10.1146/annurev.genom.6.080604.162305 [CrossRef]
- Tartaglia M, Gelb BD. Germ-line and somatic PTPN11 mutations in human disease. Eur J Med Genet. 2005;48:81–96. doi:10.1016/j.ejmg.2005.03.001 [CrossRef]
- Lee NB, Kelly L, Sharland M. Ocular manifestations of Noonan syndrome. Eye. 1992;6:328–334.
- Alexandrakis G, Saunders RA. Duane retraction syndrome. Ophthalmol Clin North Am. 2001;14:407–417. doi:10.1016/S0896-1549(05)70238-8 [CrossRef]
- Engle EC. The genetic basis of complex strabismus. Pediatr Res. 2006;59:343–348. doi:10.1203/01.pdr.0000200797.91630.08 [CrossRef]
- Traboulsi EI. Congenital cranial dysinnervation disorders and more. J AAPOS. 2007;11:215–217. doi:10.1016/j.jaapos.2007.04.007 [CrossRef]
- Schwartz DE. Noonan’s syndrome associated with ocular abnormalities. Am J Ophthalmol. 1972;73:955–960.
- Vincent AL, Watkins WJ, Sloan BH, Shelling AN. Blepharophimosis and bilateral Duane syndrome associated with a FOXL2 mutation. Clin Genet. 2005;68:520–523.
- Chung M, Stout JT, Borchert MS. Clinical diversity of hereditary Duane’s retraction syndrome. Ophthalmology. 2000;107:500–503. doi:10.1016/S0161-6420(99)00090-1 [CrossRef]
- Khan AO, Al-Hommaidi A, Al-Turkmani S. Familial ptotic lid elevation during ipsilateral abduction. J AAPOS. 2004;8:571–575. doi:10.1016/j.jaapos.2004.07.010 [CrossRef]
- Barishak YR. Embryology of the Eye and its Adnexa. New York: Karger; 2001.
- Chew E, Remaley NA, Tamboli A, Zhao J, Podgor M, Klebanoff M. Risk factors for esotropia and exotropia. Arch Ophthalmol. 1994;112:1349–1355.
Ocular Abnormalities in Noonan Syndrome
| Epicanthal folds||41|
| Downward-sloping palpebral fissures||42|
| Other (lower eyelid retraction, proptosis)||2–4|
|Anterior segment changes|
| Prominent corneal nerves||46|
| Other (keratoconus, corneal opacity, cataract, panuveitis, sclero-cornea, persistent pupillary membrane)||2–8|
| Optic disc changes||15|
| Other (tortuous vessels, retinal coloboma, myelinated nerves)||2–6|
| Refractive error||60|
| Other (nystagmus, head turn)||2–9|