Key points

Lesch-Nyhan syndrome

• •

  Genetics

  • ○

    Extremely rare, present in only 1 in 380,000 live births.

  • ○

    Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder of purine metabolism; however, up to 30% of patients carry de novo mutations. It is caused by the deficiency of hypoxanthine guanine phosphoribosyl transferase (HPRT), which is a purine salvage enzyme responsible for recycling purine bases into purine nucelotides. Specifically, it converts hypoxanthine and guanine into their respective 5′-mononucleotides.

  • ○

    The gene for HPRT ( HPRT1 ) is encoded on the long arm of the X chromosome at Xq26-Xq27. This enzyme is present in all tissues with the highest levels in the basal ganglia, which accounts for the extrapyramidal effects seen in this syndrome.

  • ○

    Because it is an X-linked disorder, male patients are almost exclusively affected. Female patients may be carriers.

  • ○

    A phenotypic spectrum exists, which is thought to be based on variability in HPRT levels and activity. Classic LNS is correlated with severe or complete HPRT deficiency. Patients with partial HPRT deficiency may present with hyperuricemia with or without neurologic and/or behavioral symptoms.

• •

  Clinical features

  • ○

    Often, children have a normal prenatal and perinatal course with development of symptoms within the first 3 to 6 months.

  • ○

    LNS has a spectrum of phenotypic presentations. However, classic LNS is characterized by aggressive and self-mutilating behavior (most commonly persistent lip, tongue, and finger biting resulting in severe avulsion injury to perioral tissues and amputation of digits), hyperuricemia, and involuntary movements with severe dystonia ( Fig. 1 A, B).

    Self-injury in Lesch-Nyhan syndrome. ( A ) Injury from persistent lip biting. ( B ) Finger amputation from self-mutilating behavior. ( C ) Patient in protective physical restraints and wheelchair device.

    ( From Visser JE, Bär PR, Jinnah HA. Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev 2000;32(2–3):467; with permission.)

  • ○

    Other features that may be present include developmental delay, megaloblastic anemia, nephropathy, and gout or tophi.

  • ○

    The first sign is the appearance of an orange or reddish sandy material in the diapers of newborns due to uric acid crystalluria and microhematuria. Additional early findings, within the first year of life, include episodic opisthotonus and the inability of a child to sit in a chair unless secured with chest or waist restraints (see Fig. 1 C).

• •

  Differential diagnosis

  • ○

    Diagnosis is made based on phenotypic presentation, elevated serum uric acid levels (greater than 4–5 mg/dL in children), and HPRT enzyme assays.

  • ○

    A wide array of disorders of purine metabolism exist that exhibit features of LNS such as gout, Arts syndrome, ribosephosphate diphosphokinase, hyperactivity, and adenylosuccinate lyase deficiency.

  • ○

    From a cognitive and neurobehavioral standpoint, LNS may mimic dyskinetic or athetoid type cerebral palsy, autism, Rett syndrome, Cornelia de Lange syndrome, or Down syndrome.

• •

  Treatment considerations for the oral and maxillofacial surgeon

  • ○

    Treatment has largely been aimed at controlling the presenting symptoms and prevention of severe injury from self-mutilation.

  • ○

    Allopurinol has been used to decrease the overproduction of uric acid. This, in turn, delays the development of renal failure. Allopurinol, however, has no effect on behavioral, neurologic, and cerebral manifestations of the syndrome. Dystonia and spasticity have been managed with GABA agonists (eg, benzodiazepines and baclofen), dopamine replacement therapy (eg, l -dopa), and deep brain stimulation to the globus pallidus. Control of self-injurious behavior has been sought with benzodiazepines, neuroleptics, antiepileptics, and chloral hydrate. Recent studies have demonstrated that the limitation of self-mutilating behavior includes a combined approach using physical restraints, behavioral treatment, and pharmacologic therapy.

  • ○

    In the event that self-mutilating behavior is refractory to medical management, alternative therapies have been proposed. Some have advocated extraction of front teeth or all remaining teeth. To avoid this invasive treatment, other investigators have advocated oral protective devices such as lip bumpers or shields, tongue shields, and occlusal bite plates or splints, which have shown some success.

  • ○

    A recent study by Chen and colleagues demonstrated regression in aggressive and self-injurious behavior and to a lesser extent dystonia with oral supplementation of S-adenosylmethionine based on its therapeutic potential to replenish the nucleotide pool in the brain.

Lesch-Nyhan syndrome

• •

  Genetics

  • ○

    Extremely rare, present in only 1 in 380,000 live births.

  • ○

    Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder of purine metabolism; however, up to 30% of patients carry de novo mutations. It is caused by the deficiency of hypoxanthine guanine phosphoribosyl transferase (HPRT), which is a purine salvage enzyme responsible for recycling purine bases into purine nucelotides. Specifically, it converts hypoxanthine and guanine into their respective 5′-mononucleotides.

  • ○

    The gene for HPRT ( HPRT1 ) is encoded on the long arm of the X chromosome at Xq26-Xq27. This enzyme is present in all tissues with the highest levels in the basal ganglia, which accounts for the extrapyramidal effects seen in this syndrome.

  • ○

    Because it is an X-linked disorder, male patients are almost exclusively affected. Female patients may be carriers.

  • ○

    A phenotypic spectrum exists, which is thought to be based on variability in HPRT levels and activity. Classic LNS is correlated with severe or complete HPRT deficiency. Patients with partial HPRT deficiency may present with hyperuricemia with or without neurologic and/or behavioral symptoms.

• •

  Clinical features

  • ○

    Often, children have a normal prenatal and perinatal course with development of symptoms within the first 3 to 6 months.

  • ○

    LNS has a spectrum of phenotypic presentations. However, classic LNS is characterized by aggressive and self-mutilating behavior (most commonly persistent lip, tongue, and finger biting resulting in severe avulsion injury to perioral tissues and amputation of digits), hyperuricemia, and involuntary movements with severe dystonia ( Fig. 1 A, B).

    Self-injury in Lesch-Nyhan syndrome. ( A ) Injury from persistent lip biting. ( B ) Finger amputation from self-mutilating behavior. ( C ) Patient in protective physical restraints and wheelchair device.

    ( From Visser JE, Bär PR, Jinnah HA. Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev 2000;32(2–3):467; with permission.)

  • ○

    Other features that may be present include developmental delay, megaloblastic anemia, nephropathy, and gout or tophi.

  • ○

    The first sign is the appearance of an orange or reddish sandy material in the diapers of newborns due to uric acid crystalluria and microhematuria. Additional early findings, within the first year of life, include episodic opisthotonus and the inability of a child to sit in a chair unless secured with chest or waist restraints (see Fig. 1 C).

• •

  Differential diagnosis

  • ○

    Diagnosis is made based on phenotypic presentation, elevated serum uric acid levels (greater than 4–5 mg/dL in children), and HPRT enzyme assays.

  • ○

    A wide array of disorders of purine metabolism exist that exhibit features of LNS such as gout, Arts syndrome, ribosephosphate diphosphokinase, hyperactivity, and adenylosuccinate lyase deficiency.

  • ○

    From a cognitive and neurobehavioral standpoint, LNS may mimic dyskinetic or athetoid type cerebral palsy, autism, Rett syndrome, Cornelia de Lange syndrome, or Down syndrome.

• •

  Treatment considerations for the oral and maxillofacial surgeon

  • ○

    Treatment has largely been aimed at controlling the presenting symptoms and prevention of severe injury from self-mutilation.

  • ○

    Allopurinol has been used to decrease the overproduction of uric acid. This, in turn, delays the development of renal failure. Allopurinol, however, has no effect on behavioral, neurologic, and cerebral manifestations of the syndrome. Dystonia and spasticity have been managed with GABA agonists (eg, benzodiazepines and baclofen), dopamine replacement therapy (eg, l -dopa), and deep brain stimulation to the globus pallidus. Control of self-injurious behavior has been sought with benzodiazepines, neuroleptics, antiepileptics, and chloral hydrate. Recent studies have demonstrated that the limitation of self-mutilating behavior includes a combined approach using physical restraints, behavioral treatment, and pharmacologic therapy.

  • ○

    In the event that self-mutilating behavior is refractory to medical management, alternative therapies have been proposed. Some have advocated extraction of front teeth or all remaining teeth. To avoid this invasive treatment, other investigators have advocated oral protective devices such as lip bumpers or shields, tongue shields, and occlusal bite plates or splints, which have shown some success.

  • ○

    A recent study by Chen and colleagues demonstrated regression in aggressive and self-injurious behavior and to a lesser extent dystonia with oral supplementation of S-adenosylmethionine based on its therapeutic potential to replenish the nucleotide pool in the brain.

Marcus Gunn syndrome

• •

  Genetics

  • ○

    Marcus Gunn syndrome is the most common congenital synkinetic eyelid disorder, with a prevalence of 4% to 6% among patients with congenital ptosis.

  • ○

    Several studies have reported that patients have a higher likelihood to have the left eye affected. The syndrome was also found to exhibit equal sex predilection.

  • ○

    Patients with Marcus Gunn syndrome may also have other eye disturbances such as amblyopia, vertical strabismus, and double elevator palsy. These eye disturbances should be addressed before any corrective ptosis surgery.

• •

  Clinical features

  • ○

    Marcus Gunn syndrome, or trigemino-oculomotor synkinesis, occurs due to an aberrant connection between the motor branches of the third division of trigeminal nerve innervating the pterygoid muscle and the fibers of the superior division of the oculomotor nerve that innervate the levator palpebrae superioris.

  • ○

    It is clinically characterized as a ptotic eyelid that is rapidly elevated on lateral excursions, opening of the mandible, whistling, sucking, blowing, smiling, speaking, and tongue movements ( Fig. 2 ).

    ( A ) Child with Marcus Gunn jaw-winking phenomenon demonstrating unilateral left upper eyelid ptosis. ( B ) Ptosis is resolved by synkinetic upper eyelid elevation with concomitant jaw opening.

    ( From Bartkowski SB, Zapala J, Wyszyńska-Pawelec G, et al. Marcus Gunn jaw-winking phenomenon: management and results of treatment in 19 patients. J Craniomaxillofac Surg 1999;27(1):26; with permission.)

• •

  Differential diagnosis

  • ○

    A differential diagnosis to consider is Marin-Amat syndrome. This synkinetic eyelid disorder is characterized as involuntary eyelid closure on jaw opening. It occurs due to an aberrant connection between the facial nerve and the trigeminal nerve.

• •

  Treatment considerations for the oral and maxillofacial surgeon

  • ○

    Eye shields or eye protection should be used during dental or oral and maxillofacial surgery procedures because the eye will open when the mouth opens.

  • ○

    In a mild case that is not bothersome to the patient, no intervention can be elected.

  • ○

    In a case in which there is moderate-to-severe ptosis, or if the patient has esthetic concerns, a surgical intervention can be considered.

  • ○

    Several corrective procedures exist, including the Fasanella-Servat procedure, bilateral levator muscle excision followed by bilateral fascia lata brow suspension, or bilateral frontalis suspension with levator excision on the affected side. Other surgical procedures exist; however, it is beyond the scope of this article to describe all methods.

Cavernous sinus syndrome

• •

  Genetics

  • ○

    Cavernous sinus syndrome has no genetic basis; however, multiple causes for the syndrome exist and many of these have underlying genetic causes. Discussion of each is beyond the scope of this article.

  • ○

    A study done by Keane investigated the most common causes of cavernous sinus syndrome. He found that, among 151 subjects (45 subjects, 30%), tumors were the most frequent cause of this syndrome. The second-most common cause (36 subjects, 24%) was trauma. Self-limited inflammation was the third-most frequent cause (34 subjects, 23%). Carotid aneurysms and fistulas, infection, and other causes composed the remaining 12%.

• •

  Clinical features

  • ○

    The cavernous sinus is a paired structure that lies on either side of the sella turcica and lateral to the pituitary gland. The contents include an extradural plexus surrounded by a dural fold and the internal carotid artery with associated sympathetic plexus ( Fig. 3 ). The abducens nerve runs lateral to the internal carotid artery but medial to the oculomotor nerve (see Fig. 3 ). Within the lateral dural border of the cavernous sinus lie the oculomotor nerve, trochlear nerve, ophthalmic division of trigeminal nerve and maxillary division of the trigeminal nerve (superior to inferior) (see Fig. 3 ). Venous drainage is from the superior and inferior orbital veins.

    Coronal section through the cavernous sinus. Meningeal layer in orange, periosteal layer in green. Car. A., carotid artery; CN, cranial nerve; Pit., pituitary; Sphen., sphenoid; V1, V2, V3, cranial nerves V1, V2, V3.

    ( From Campero A, Campero AA, Martins C, et al. Surgical Anatomy of the dural walls of the cavernous sinus. J Clin Neurosci 2010;17(6):747; with permission.)

  • ○

    The main symptoms of cavernous sinus syndrome are ophthalmoplegia, sensory loss of the ophthalmic and maxillary divisions of the trigeminal nerve distribution, with or without the presence of lid ptosis, anhidrosis, and miosis on the affected side ( Fig. 4 ).

    ( A ) Patient presented with a left intracavernous internal carotid aneurysm (ICICA) occupying the posterior third of the cavernous sinus, demonstrating left-globe proptosis, abducens nerve palsy, and sympathetic nerve impairment with partial Horner syndrome. ( B ) Patient presented with a right ICICA occupying the anterior third of the cavernous sinus, demonstrating partial right eyelid ptosis and restricted upward gaze of right globe significant for isolated right oculomotor superior division palsy.

    ( From Silva MN, Saeki N, Hirai S, et al. Unusual cranial nerve palsy caused by cavernous sinus aneurysms: clinical and anatomic considerations reviewed. Surg Neurol 1999;52(2):144–5; with permission.)

  • ○

    Other symptoms may include orbital congestion and proptosis and periorbital edema, depending on the cause of the syndrome.

• •

  Differential diagnosis

  • ○

    The differential diagnosis for cavernous sinus syndrome includes superior orbital fissure syndrome, orbital apex syndrome, Horner syndrome, carotid canal syndrome, and Tolosa-Hunt syndrome.

• •

  Treatment considerations for the oral and maxillofacial surgeon

  • ○

    Treatment of this syndrome is aimed at identifying and managing the underlying condition.

  • ○

    Broad categories of diseases resulting in the clinical presentation of cavernous sinus syndrome include bacterial and fungal infection, noninfectious inflammation, vascular lesions, and neoplasms.

  • ○

    Several infectious processes may result in the development of cavernous sinus thrombosis. Infections of the midface (ie, nasal furuncles) can enter the facial vein and pterygoid plexus and be carried to the cavernous sinus. Staphylococcus aureus is the most common microbe in this setting. Acute or chronic sphenoid and ethmoid sinusitis may result in cavernous sinus thrombosis. Common pathogens include Staphylococcus aureus and Streptococcus pneumoniae, as well as other anaerobic streptococcus species. In the case of chronic sinusitis (ie, rhinocerebral aspergillosis and mucormycosis), the most common fungal pathogens include Aspergillus and Mucorales . Treatment includes appropriate antifungal or antimicrobial therapy, endoscopic drainage, and anticoagulation (low molecular weight heparin or warfarin).

  • ○

    Of particular clinical importance to the surgeon are odontogenic infections with extension into deep fascial spaces. For instance, infections of the masticator, canine, buccal, or lateral pharyngeal spaces can result in life-threatening complications such as cavernous sinus thrombosis and erosion into the internal carotid artery. Pathogens most commonly involved include S treptococcus species, Fusobacterium , and Bacteroides . Management includes surgical incision and drainage of the affected spaces, in addition to appropriate antimicrobial therapy.

  • ○

    An example of a noninfectious cause is an inflammatory pseudotumor that is responsive to steroid administration.

  • ○

    Carotid-cavernous fistulas may be divided into direct or indirect fistulas. Direct fistulas demonstrate direct continuity between the cavernous segment of the carotid artery and the cavernous sinus. They form after closed head injuries or ruptured aneurysms and present with a classic triad of chemosis, pulsatile exophthalmos, and a bruit over the affected eye. Management includes endovascular treatment using detachable balloons, onyx (ethylene vinyl alcohol copolymer), or coils. Indirect fistulas form a shunt with the meningeal branches of the carotid artery and often spontaneously resolve.

  • ○

    Giant internal carotid aneurysms (>2.5 cm) cause pain and ophthalmoplegia. Endovascular embolization or coiling may be indicated in select patients (see Fig. 1 ).

  • ○

    Neoplasms that may cause cavernous sinus syndrome include pituitary adenomas, malignancy with perineural spread (ie, nasopharyngeal carcinoma [NPC]), meningioma, and hemangiomas. These lesions usually require excision.

Superior orbital fissure syndrome

• •

  Genetics

  • ○

    This syndrome has no genetic predilection.

  • ○

    Although the syndrome is fairly uncommon, causes of superior orbital fissure syndrome include tumors in the retrobulbar space, retrobulbar hematomas, infection in the cavernous sinus or retrobulbar space, as well as facial trauma.

  • ○

    The incidence of traumatic superior orbital fissure in cases involving facial fractures was reported to be 0.3%.

  • ○

    In the case of blow-in fractures of the orbit, the incidence of superior orbital fissure syndrome was reported to be as high as 10%.

  • ○

    In a study by Chen and colleagues, four cases of carotid-cavernous sinus fistula were confirmed by angiography out of 33 cases of superior orbital fissure syndrome.

• •

  Clinical features

  • ○

    It is important to note the anatomy of the superior orbital fissure because its contents reflect the clinical features of the syndrome. The superior orbital fissure contains the trochlear, lacrimal, and frontal nerves, as well as the superior ophthalmic vein, the superior and inferior branches of the oculomotor nerve, the nasociliary nerve, and the abducens nerve ( Fig. 5 ).

    Diagram displaying the contents of the superior orbital fissure. a, artery; n, nerve; v, vein.

    ( From Anderson BC, McLoon LK. Cranial nerves and autonomic innervation in the orbit. In: Dartt DA, editor. Encyclopedia of the eye. Oxford (United Kingdom): Academic Press; 2010. p. 539; with permission.)

  • ○

    Superior orbital fissure syndrome is characterized by ptosis of the upper eyelid, ophthalmoplegia, hypoesthesia of the ipsilateral V1 dermatome, proptosis, and mydriasis ( Fig. 6 ). Additional clinical signs include lacrimal hyposecretion and loss of the corneal reflex.

    Superior orbital fissure syndrome demonstrates ptosis, pupillary dilation, and ophthalmoplegia. ( A ) Right lid ptosis. ( B ) Radiograph showing a fracture ( red arrows ) causing compression of superior orbital fissure. ( C ) Right pupillary dilation. ( D – F ) Right ophthalmoplegia.

    ( From Turvey TA, Golden BA. Orbital Anatomy for the Surgeon. Oral Maxillofac Surg Clin North Am 2012;24(4):528; with permission.)

• •

  Differential diagnosis

  • ○

    If there is visual acuity involvement, orbital apex syndrome should be considered. Cavernous sinus syndrome should also be considered if there is involvement of V2 dermatome instead of V1 division of the trigeminal nerve.

• •

  Treatment considerations for the oral and maxillofacial surgeon

  • ○

    Appropriate imaging should include CT scan with angiography and/or magnetic resonance angiography if a carotid-cavernous sinus fistula is suspected. If a carotid-cavernous sinus fistula is diagnosed, prompt embolization is recommended.

  • ○

    Obtain ophthalmologic consultation for patients with associated globe injuries.

  • ○

    Treatment modalities in the literature have been controversial. There are advocates for high-dose steroid therapy and surgical decompression, as well as for no intervention.

  • ○

    In the event of facial fractures requiring repair, open reduction and internal fixation may generally be performed without fear of causing a worsening of associated cranial nerve palsies.

  • ○

    Early repair of orbital blow-in fractures had a favorable outcome in subjects with associated superior orbital fissure syndrome.