Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects.

Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.

A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome.

Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic factors significantly contribute to early-onset FSGS, but the etiologies of most adult cases remain unknown. Genetic studies of monogenic syndromic FSGS exhibiting extra-renal manifestations have uncovered an unexpected biological role for genes in the development of both podocytes and other cellular lineages. To help define these roles, we studied two unrelated families with FSGS associated with Duane Retraction Syndrome, characterized by impaired horizontal eye movement due to cranial nerve malformation. All four affected individuals developed FSGS and Duane Retraction Syndrome in their first to second decade of life, manifested as restricted abduction together with globe retraction and narrowed palpebral fissure on attempted adduction. Hypoplasia of the abducens nerves and hearing impairment occurred in severely affected individuals. Genetic analyses revealed that affected individuals harbor a rare heterozygous substitution (p.Leu239Pro) in MAFB, a leucine zipper transcription factor. Luciferase assays with cultured monocytes indicated that the substitution significantly reduced transactivation of the F4/80 promoter, the known MAFB recognition element. Additionally, immunohistochemistry indicated reduced MAFB expression in the podocytes of patients. Structural modeling suggested that the p.Leu239Pro substitution in the DNA-binding domain possibly interferes with the stability of the adjacent zinc finger. Lastly, podocytes in neonatal mice with p.Leu239Pro displayed impaired differentiation. Thus, MAFB mutations impair development and/or maintenance of podocytes, abducens neurons and the inner ear. The interactions between MAFB and regulatory elements in these developing organs are likely highly specific based on spatiotemporal requirements.

Extraocular muscle dysinnervation disorder resembling Duane retraction syndrome in a 9-month-old French Bulldog.

A 9-month-old French Bulldog was presented with a chronic history of lateral strabismus and intermittent third eyelid protrusion in the left eye. The neuro-ophthalmological examination revealed mild ptosis of the left upper eyelid, mild lateral strabismus, and external ophthalmoparesis of the left eye. Retraction and ventral deviation of the left eye globe with protrusion of the third eyelid and elevation of the upper eyelid were elicited on attempted voluntary adduction of the left eye. Hematology, serum biochemistry, serology for infectious diseases, magnetic resonance of the head, and cerebrospinal fluid analysis did not reveal significant abnormalities. Forced duction test did not show signs of mechanical restriction in ocular motility. A suspected congenital cranial dysinnervation disorder resembling Duane retraction syndrome in humans was diagnosed based on the typical clinical signs and exclusion of structural abnormalities. The clinical signs remained stable for 9 months until the time of writing this report.

[Using the superficial temporal fascia flap in orbital surgery]. / Utilisation du lambeau de fascia temporalis superficialis en chirurgie orbitaire.

The superficial temporal fascia flap gives a fine malleable well vascularized tissue and can be used as a pedicled or a free flap to cover large areas of loss of substance. Its dissection needs a period of training. Its use in orbital surgery is rare. However when it is about an anophthalmic socket following radiotherapy with orbital retraction syndrome, it provides tissue of good quality. This could allow later reconstruction by mucous grafts. When used on cavities of exenteration it allows fast re-epithelialisation even post-radiotherapy, while allowing the monitoring of the cavity and in particular the early detection of any tumor recurrence. Its use is advantageous in unfavorable conditions especially after radiotherapy.

Case report: Duane Retraction Syndrome associated with hand anomaly.

Duane Retraction Syndrome is a congenital eye movement disorder characterized by a failure of cranial nerve VI to develop normally, resulting in restriction or absence of abduction, restricted adduction and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. Patients with Duane Retraction Syndrome appear to have a significant increase in the number of associated congenital malformations. In the present paper, the authors report a case of Duane Retraction Syndrome with a unique hand abnormality not reported previously.

Atypical association of Duane retraction syndrome and Bardet Biedl syndrome.

Duane's retraction syndrome (DRS) includes changes in palpebral fissure width along with restriction of ocular motility. Bardet Biedl syndrome (BBS) includes presence of retinitis pigmentosa (RP) with obesity, mental retardation, polydactyly and renal abnormalities. We report a case of rare association of DRS with BBS in a seven-year-old child. The ocular motility examination revealed left DRS with esotropia. Fundus examination revealed findings characteristic of an atypical retinitis pigmentosa. The electro-retinogram waveforms were extinguished both for rods and cones. He was diagnosed as a case of BBS on the basis of the ophthalmological findings plus association with the systemic features of obesity, polydactyly, hypogonadism, mental retardation and renal abnormalities. This case gives further evidence of the fact that BBS may be associated with abnormalities of eye movements.

Duane retraction syndrome in a patient with Duchenne muscular dystrophy.

PURPOSE: We describe the clinical features of a boy with bilateral Duane retraction syndrome (DRS), Duchenne muscular dystrophy (DMD), and other medical problems. METHODS: The child was followed-up for five years; his chart was reviewed, including the results of a muscle biopsy and genetic testing. Multiplex ligation-dependent probe amplification (MLPA) was used to interrogate deletions/duplications in the dystrophin gene. RESULTS: The proband had bilateral DRS with otherwise normal ocular motility; he also had developmental delay, mild mental retardation, and seizures. Clinical diagnosis of DMD included progressive proximal weakness, highly elevated creatine kinase levels, and a muscle biopsy showing significant dystrophic changes including contracted, degenerative, and regenerative fibers, and negative dystrophin immunostaining. MLPA documented duplication of exons 3 and 4 of the dystrophin gene. CONCLUSIONS: This boy is the third patient to be reported with DRS and DMD, the second with bilateral DRS and the only one with other neurologic features. Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS) in DMD, leaving open the question of whether this co-occurrence is the result of the genetic muscle abnormality, CNS effects caused by dystrophin mutations, or chance.

Benedikt and "plus-minus lid" syndromes arising from posterior cerebral artery branch occlusion.

A 53-year-old man was admitted with diplopia, right ptosis, left lid retraction, mild left sided weakness and involuntary movements. Neurological examination revealed plus-minus lid and Benedikt's syndromes together. Magnetic resonance imaging (MRI) showed two distinct mesencephalic infarctions in territories of paramedian and pedincular perforating arteries. Magnetic resonance angiography (MRA) showed severe stenosis of proximal segment of the right posterior cerebral artery (PCA). Rare clinical presentations such as Benedikt and plus-minus syndromes can be seen together and be due to stenosis of the posterior cerebral artery with specific regional infarctions.

[Duane's syndrome--etiopathogenesis, clinical features and diagnosis]. / Sindromul Duane--consideratii etiopatogenice clinice si de diagnostic.

Duane syndrome is a congenital disease also known as congenital retraction syndrome or Stilling-Turk-Duane retraction syndrome. There are three types of Duane syndrome; their variability is given by the aberrant innervation of the lateral rectus muscle. The symptoms of the disease were described and they are all known, but the etiology and the pathology remain unclear. Although Duane syndrome was considered as a pure local myogenic phenomenon (the lateral rectus muscle fibrosis), the modern theory is the absence of the abducens nuclei. Various theories have been put forward on the basis of data collected from surgical, autopsy and electromyography studies. The most frequent and terrifying differential diagnosis is the VI nerve palsy and the symptoms of Duane syndrome suggest an intracranial disease, so we understand the parents and patient fear. That's why is very important to explain them the causes and the consequences of the disease and to educate the patients to obtain the optimal functional and mental comfort. Finally, we have in mind one, at least subjective, question: why is the abducens nerve nucleus affected and how?

Duane's retraction syndrome.

Duane's retraction syndrome (DRS) has been a recognized clinical entity for nearly a century. It is a clinically well described ocular disorder consisting of retraction of the globe with narrowing of the lid fissure in attempted adduction, frequent abduction deficiency with variable limitation to adduction, and upshoot and/or downshoot of the affected eye on adduction. Among strabismus patients the incidence of DRS is probably not more than 5%. Most cases are sporadic, but familial cases have been estimated at 10% by most authors. Numerous theories concerning the etiology and pathogenesis of DRS have been proposed, including agenesis of the abducens nucleus, but the majority of investigators concur that the characteristic findings are best explained by a paradoxical innervation of the lateral rectus muscle, which subsequently causes a cocontraction of the horizontal rectus muscles. The frequent association of DRS with other congenital anomalies suggests a teratogenic event occurring between the fourth to eighth week of gestation as an etiological factor. In this review historical aspects and theories of the syndrome are studied and statistical data are compiled and analyzed. Clinical features, differential diagnoses and variants of the syndrome are examined. Testing and treatment objectives are discussed.

Vertical Duane's retraction syndrome.

PURPOSE: We report three patients with a rare variant of Duane's retraction syndrome. METHODS: Eye movements were recorded by electro-oculography. One patient underwent electro-myography. RESULTS: All patients showed V-incommitance and twitch abduction on vertical saccades. Electromyography showed lateral rectus muscle firing activity during upgaze and downgaze. CONCLUSION: Our patients showed synergistic innervation between the lateral rectus muscle and ipsilateral vertical acting muscles documented by electromyography.

Duane retraction syndrome associated with Rubinstein-Taybi syndrome.

The authors present a case report of Duane retraction syndrome (DRS) associated with Rubinstein-Taybi syndrome (RTS). RTS is a multisystem condition characterized by psychomotor developmental delay, broad thumbs and great toes, short stature, and characteristic facies with a beaked nose. DRS is an ocular disorder characterized by retraction of the globe with narrowing of the palpebral fissure in attempted adduction, with abduction and/or adduction deficiency, and, frequently, upshoot or downshoot of the affected eye on adduction. The case report described represents the first reported case of DRS associated with RTS, an association not previously recognized. This association raises the possibility that the abnormal CNS development in RTS may occasionally involve the ocular motor nerves.

Congenital crocodile tears: a key to the aetiology of Duane's syndrome.

The occurrence from birth of copious lacrimation on eating in some patients with Duane's syndrome suggests that both are caused by dysgenesis or a lesion in the vicinity of the abducens nucleus in the pons.

Duane's retraction syndrome associated with optic nerve hypoplasia.

A patient with unilateral Duane's retraction syndrome and optic nerve hypoplasia is presented. The occurrence of these anomalies not previously reported together in a patient, supports the hypothesis of a disturbance in embryogenesis during the second gestational month as the etiology of the retraction syndrome.

Acquired retraction syndrome associated with orbital metastasis.

A patient with metastatic disease of the lateral orbit developed an acquired motility defect similar to Duane's retraction syndrome. An acquired retraction syndrome, unlike the congenital form, is due either to mechanical defects of the orbit and eye or to neurologic disease. The direction of gaze in which the retraction occurs is the clinical clue to the location of the restricting element in the mechanically caused cases.

Bilateral Duane's syndrome associated with crocodile tears.

The rare association of two syndromes of paradoxical innervation, bilateral Duane's retraction syndrome and congenital crocodile tears is presented. This association assumes a central localization to explain both anomalies.

Duane's retraction syndrome associated with morning glory syndrome.

A 9-year-old boy with Duane's retraction syndrome and morning glory syndrome is presented. The right eye showed a grayish-pink optic disc, which had a deep excavation containing a white mass in its center and was surrounded by an annulus of pigment disturbance, i.e., consistent with the features of morning glory syndrome. The left eye had a congenital disturbance of ocular motility, which was typical of Duane's retraction syndrome. This is probably the first report of the association of Duane's retraction syndrome and morning glory syndrome. It is hypothesized that a noxious stimulus given at around two months of gestation was responsible for this rare association.

Marcus Gunn jaw winking and Duane's retraction syndrome.

A three-month-old female presented with the unusual findings of Marcus Gunn Jaw Winking Phenomenon and Duane's Retraction Syndrome in the same eye. In considering suggested etiologies for these two disorders, a misdirection of peripheral innervation would account for both these entities co-existing. In reviewing the ophthalmic literature, the association of these disorders was first described around the turn of the century but much less in recent years.

[Bilateral meningiomas of the optic nerves associated with partial unilateral Duane's syndrome]. / Méningiomes bilatéraux des nerfs optiques associés a un syndrome de Duane partiel unilatéral.

A 34 years old man, with right eye blindness since childhood, presented with a decreased vision of the left eye 28 years later. Apart from bilateral papillary atrophy, right blindness and decreased left visual acuity, neuro-ophthalmological examination revealed a partial Duane's retraction syndrome on the right. Optic canal X-rays and cerebral CT-Scan revealed calcified meningiomas of both optic nerves. The diagnosis was confirmed at surgery. Cases of bilateral optic nerve meningioma are reviewed. The difficulties of diagnosis, the usefulness of the CT-Scan, the poor prognosis of the disease, even with surgery and radiotherapy are considered. No explanation was found for the association of the tumors with Duane's retraction syndrome.