The Journal of Craniofacial Volume 28, Number 2, March 2017 Brief Clinical Studies

2. Losee JE, Kirschner RE, Whitaker LA, et al. Congenital nasal anomalies: a classification scheme. Plast Reconstr Surg 2004;113: 676–689 3. Kantaputra PN. Laurin-Sandrow syndrome with additional associated manifestations. Am J Med Genet 2001;98:210–215 4. Laurin CA, Favreau JC, Labelle P. Bilateral absence of the radius and tibia with bilateral reduplication of the ulna and fibula. A case report. J Bone Joint Surg Am 1964;46:137–142 5. Sandrow RE, Sullivan PD, Steel HH. Hereditary ulnar and fibular dimelia with peculiar facies. A case report. J Bone Joint Surg Am 1970;52:367–370 6. Martinez-Frias ML, Alcaraz M, Espejo P, et al. Laurin-Sandrow syndrome (mirror hands and feet and nasal defects): description of a new case. J Med Genet 1994;31:410–412 7. Lohan S, Spielmann M, Doelken SC, et al. Microduplications encompassing the Sonic Hedgehog limb enhancer Zrs are associated with Haas-Type polysyndactyly and Laurin-Sandrow syndrome. Clin Genet 2014;86:318–325 8. deAlmeida VL, Alcaro RA, Haider Z, et al. The effect of nasal occlusion on the initiation of oral breathing in preterm infants. Pediatr Pulmonol FIGURE 3. Extremity clinical photos and imaging. 1994;18:374–378 9. Miller MJ, Martin RJ, Carlo WA, et al. Oral breathing in newborn infants. DISCUSSION J Pediatr 1985;107:465–469 Laurin–Sandrow syndrome is a rare autosomal dominant disorder characterized by polysyndactyly of hands and feet in a mirror fashion, absence of the radius and tibia with duplicated ulna and fibula, and nasal defects.3 It was originally described by Laurin et al4 in 1964, with no mention of nasal abnormalities. Sandrow Pediatric Sialadenosis Due to et al5 later described 2 more cases in 1970, 1 of which had nasal defects. Martinez-Frias et al6 reported a new case and suggested in Valproic Acid 1994 that this entity was referred to as Laurin–Sandrow syndrome. y z In a recent clinical report and review of literature, it is proposed that Hatice Derin, MD, Serhan Derin, MD, Pembe Oltulu, MD, ¨ § LSS must have the following criteria: tetramelic and symmetric Orhan Ozbek, MD, and Hu¨seyin C¸ aksen, MD polysyndactyly with nasal anomalies.1 Thus, leaving out of the definition any reported case of unilateral extremity defect, this Abstract: Sialadenosis is a rare entity characterized by bilateral leaves only 14 described patients in the literature. diffuse, painless swelling of the parotid glands. Its etiology is not It is thought that the embryonic developmental error occurs clear; however, it may occur due to adverse effects of some drugs. around the fifth and sixth weeks, and the phenotypic variability is To our knowledge, sialadenosis due to valproic acid has not been 5 due to differences in timing of onset. The genetic basis for LSS is reported in the literature up to date in any child. In this article, the unknown. However, recent literature indicates that the genetic authors presented a child who developed sialadenosis due to cause of the disease is microduplications within the Sonic hedgehog valproic acid, and improved after stopping use of the drug. limb enhancer ZRS region on chromosome 7q36.7 Lohan et al explain that the size of microduplications within ZRS correlates with the phenotype, with smaller duplications resulting in more Key Words: Adverse drug reaction, , complex limb deformities. There is no description in the literature valproic acid as to what genes are involved in the nasal defects. 2 Losee et al classified nasal anomalies into 4 different types. The ialadenosis (sialosis) is a rare disorder characterized by chronic, deformities present in the LSS cases described include bifid colu- S bilateral, diffuse, noninflammatory, and non-neoplastic swel- mella, flat nasal bridge, unfused nares, hypoplastic nasal skeleton, ling of the major salivary glands, and particularly parotid gland.1 It and redundant nasal tissue. In our patient’s case, there was redun- has been associated with various nutritional and hormonal disorders dant nasal soft tissue, a prominent anterior nasal spine, and partial ossification of the lower lateral cartilages. Upon literature review, From the Pediatric Department, Meram Faculty of , we were unable to find a case involving ossification of the Necmettin Erbakan University, Konya; yOtorhinolaryngology Depart- nasal cartilages. ment, Faculty of Medicine, Mug˘la Sitki Koc¸man University, Mug˘la; Neonates are known to be obligate nasal breathers, but have been zPathology Department, Meram Faculty of Medicine, Necmettin Erba- shown to transition to oral breathing in cases of complete nasal kan University; and § Department, Meram Faculty of Medi- obstruction.8,9 Our patient was unable to adapt to obstructed nasal cine, Necmettin Erbakan University, Konya, Turkey. airways, requiring intubation. The early surgery performed in this Received June 18, 2016. case helped open the anterior nasal passages, creating unobstructed Accepted for publication September 22, 2016. Address correspondence and reprint requests to Hatice Derin, MD, Yunus airflow, resulting in successful extubation, with the added benefit of Emre Mah, Necmettin Erbakan U¨ niversitesi, Meram Tip Faku¨ltesi normalization of nasal esthetics. Hastanesi, 42000 Konya, Turkey; E-mail: [email protected] This study was presented as a poster in 18th National Pediatric Neurology REFERENCES Congress, Antalya, April 2016. The authors report no conflicts of interest. 1. Marino-Enriquez A, Lapunzina P, Omenaca F, et al. Laurin-Sandrow Copyright # 2016 by Mutaz B. Habal, MD syndrome: review and redefinition. Am J Med Genet A ISSN: 1049-2275 2008;146A:2557–2565 DOI: 10.1097/SCS.0000000000003303

# 2017 Mutaz B. Habal, MD e127 Copyright © 2017 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited. Brief Clinical Studies The Journal of Craniofacial Surgery Volume 28, Number 2, March 2017

tests, and immunoglobulin levels were in normal limits. The patient did not have eating disorders, malnutrition, or exposure to radio- active iodine. Tru-cut biopsy of the right parotid gland was per- formed. Histopathological examination revealed significant hydropic degeneration in epithelial cells of the acini; however, there was no inflammatory infiltrate (Fig. 1C). Electroencephalo- graphy of the patient was compatible with electrical status epilep- ticus in sleep, and the serum valproic acid level of the patient was 81 mg/mL (normal limit 50–100 mg/mL). The patient was diag- nosed with sialadenosis associated with use of valproic acid, and valproic acid was stopped. The doses of other antiepileptics were increased. The parotid swelling of the patient decreased signifi- cantly at the 4th month of follow-up visit (Fig. 1D).

DISCUSSION Sialadenosis is a rare disorder characterized by diffuse, noninflam- matory, non-neoplastic enlargement of the major salivary glands.5 Its etiology is not clear; however, it has been supposed that severe metabolic or hormonal disorders result in peripheral autonomic neuropathy, and degenerative changes in the myoepithelial cells FIGURE 1. (A) Bilateral parotid sialadenosis at the time of admission. (B) surrounding the acini.6 As a result, the secretory granules accumu- Bilateral parotid enlargement in T1-weighted magnetic resonance imaging late in the cells, and cause diffuse enlargement of the salivary with contrast. (C) Light microscopic appearance of the sialadenosis in the 5 parotid gland (100 and 400). Hydropic degeneration in the cells that gland. The disease was associated with some endocrinological constitute the acini. (D) Appearance of the parotid glands 4 months after diseases such as diabetes mellitus and hypothyroidism, nutritional stopping valproic acid treatment. disorders such as anorexia, bulimia, and kwashiorkor, and some other diseases such as sarcoidosis, tuberculosis, syphilis, AIDS, leukemia, and Sjogren syndrome.7 It rarely appears as the adverse including chronic malnutrition, obesity, alcoholism, diabetes, 2,3 effects of some drugs including methyldopa, clonidine, reserpine, hypothyroidism, and eating disorders. A number of medications nifedipine, tricyclic , insulin, and nitrofurantoin.7,8 including antihypertensive drugs have been accused in the etiology To our knowledge, sialadenosis associated with valproic acid was of the disease.4 All patients are adults since most of the factors 5 reported in 2 adults at 23 and 26 years of age; however, it has not accused in etiology are usually seen in adulthood. In this article, the been reported in children.7,8 authors presented a rare pediatric sialadenosis that occurred due to Valproic acid inhibits GABA transaminase, and increases the use of valproic acid. To our knowledge, this is the first pediatric GABA level in the synapsis. It also inhibits neuronal uptake of patient in the literature. GABA, and increases postsynaptic efficiency of GABA. It may open potassium channels of the neuronal membranes, and cause CLINICAL PRESENTATION hyperpolarization.9 The mechanism of valproic acid-related siala- A 9-year-old boy diagnosed with epilepsy and cerebral palsy denosis was hypothesized as an increase in the excitation threshold admitted with bilateral parotid swelling that had been present for of the sympathetic nervous system, and inhibition of the protein 2 months. The parents of the child were relatives (first degree secretion.7 cousins). The prenatal and natal histories of the patient were normal. Other possible causes of bilateral parotid gland enlargement His postnatal history revealed that he had his first afebrile convul- should be ruled out including infections, autoimmune and granu- sion when he was 55 days old, and stayed in the intensive care unit lomatous diseases, neoplasia, etc. to diagnose sialadenosis.5 for 15 days. He was on valproic acid (Convulex, 35 mg/kg per d, In sialadenosis, light and electron microscopic examinations started 1 year ago) levetiracetam (Keppra, 32 mg/kg per d, for 2 show enlargement of acini and increase in intracytoplasmic years), and diazepam (Nervium, 1 mg/kg per d, for 6 months) due to secretion granules, but infection findings are not seen.7 refractory epilepsy. The physical examination of the patient Isoprenaline, low-dose oral , and pilocarpine revealed that his weight was 25 kg (10–25.p), his height was have been used in the treatment of sialadenosis, but their efficacies 115 cm (<3.p). He had mental retardation, diffuse, bilateral, sym- are low. Parotidectomy may be performed if the cosmetic deformity metrical parotid gland swelling, and increased deep tendon reflexes is intolerable, and the patient does not respond to conservative (Fig. 1A). Other findings were normal on systemic examination. treatment.7,10 Head and neck magnetic resonance imaging with contrast showed In this manuscript, we presented a child with bilateral parotid bilateral diffuse enlargement of the parotid glands, being more gland sialadenosis, most probably developed due to valproic acid. significant on the right side (Fig. 1B). There were no calculi. Parotid Our patient had been using valproic acid for 1 year before siala- ultrasonography revealed that anteroposterior diameter of the left denosis appeared; however, this duration was several months and parotid gland was 40 mm, its craniocaudal diameter was 45 mm, and 3 years in other clinical reports in the literature.7,8 Absence of any those values were 43 and 45 mm for the right parotid gland. There systemic diseases or infection that could be associated with siala- were no focal lesions or increased blood flow. The results of the denosis implicated that the disease was associated with the adverse laboratory tests were as follows: white blood cell: 7400/mm3, effects of drugs. We supposed that sialadenosis was associated with hemoglobin: 11.4 g/dL, glucose: 72 mg/dL, C-reactive protein valproic acid when we considered the medications used by the was negative, and erythrocyte sedimentation rate was 9 mm/h. patient, and valproic acid was stopped. The histopathology of the IgM and IgG, anti-HIV, toxoplasma IgM and IgG, Borrelia parotid gland was in correlation with the findings of sialadenosis. IgM, Brucella, syphilis, PPD, SS-A and SS-B, ANCA, ACE, RF, Improvement of parotid swelling after stopping valproic acid and ANA were all negative. Thyroid function tests, liver function supported our diagnosis. e128 # 2017 Mutaz B. Habal, MD Copyright © 2017 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited. The Journal of Craniofacial Surgery Volume 28, Number 2, March 2017 Brief Clinical Studies

In conclusion, sialadenosis should be kept in mind in children idiopathic skeletal hyperostosis. Multidetector computed tomogra- who admit with diffuse enlargement of the major salivary glands phy accuracy showed compression to the hypopharyngeal air and diagnosis of epilepsy, and use of valproic acid should be column by the Eagle syndrome and diffuse idiopathic skeletal questioned. It should be kept in mind that the disorder may improve hyperostosis. just by stopping use of the medication.

REFERENCES Key Words: Diffuse idiopathic skeletal hyperostosis, Eagle 1. Scully C, Baga´n JV, Eveson JW, et al. Sialosis: 35 cases of persistent syndrome, hypopharyngeal compression, multidetector computed parotid swelling from two countries. Br J Oral Maxillofac Surg tomography 2008;46:468–472 2. Chen S, Paul BC, Myssiorek D. An algorithm approach to bilateral relation between diffuse idiopathic skeletal hyperostosis of the parotid enlargement bilateral parotid disease. Otolaryngol Head Neck A cervical spine and ossification of the styloid process has been Surg 2013;148:732–739 previously reported.1 This condution can very rarely present with 3. Gu¨nbey HP, Gu¨nbey E, Tayfun F, et al. A rare cause of unilateral parotid gland swelling: compensatory hypertrophy due to the aplasia of the as a result of compression of the hypopharynx. This report contralateral parotid gland. J Craniofac Surg 2014;25:e265–e267 showed the importance of multidetector computed tomography 4. Sanan A, Cognetti DM. Rare parotid gland diseases. Otolaryngol Clin N (MDCT) in a patient that involved a coincidence of Eagle syndrome Am 2016;49:489–500 and diffuse idiopathic skeletal hyperostosis. In this patient, MDCT 5. Wen Y, Goo HW. Sonographic and CT findings of sialadenosis in a child showed compression to the hypopharyngeal air column by the Eagle with leukemia. Korean J Radiol 2012;13:634–636 syndrome and diffuse idiopathic skeletal hyperostosis. 6. Ihrler S, Rath C, Zengel P, et al. Pathogenesis of sialadenosis: possible role of functionally deficient myoepithelial cells. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol 2010;110:218–223 CLINICAL REPORT 7. Mauz PS, Mo¨rike K, Kaiserling E, et al. Valproic acid-associated A 56-year-old man was referred to our radiology department with sialadenosis of the parotid and submandibular glands: diagnostic and the complaints of cervical bolus sensation and intermittent dyspha- therapeutic aspects. Acta Otolaryngol 2005;125:386–391 gia for 10 months. There was no history of surgery and trauma. The 8. Reisser C, Maier H. Sialadenosis caused by long-term valproate oral examination revealed a protrusion through the posterior wall of medication. Laryngorhinootologie 1991;70:384–386 the hypopharynx. In nonenhanced MDCT of the neck, a multiplanar 9. Oguz K. In: Kayaalp O, Dalkara T, eds. Medical Pharmacology. 10th reconstruction image at the coronal plane revealed long styloid ed Ankara: Hacettepe-Tas; 2002:1017–1018 10. Pape SA, MacLeod RI, McLean NR, et al. Sialadenosis of the salivary processes (Fig. 1A). The patient was diagnosed Eagle syndrome. glands. Br J Plast Surg 1995;48:419–422

Coincidence of Eagle Syndrome and Diffuse Idiopathic Skeletal Hyperostosis Presenting With Dysphagia as a Result of Compression of the Hypopharynx Vahit Mutlu, MD and Hayri Ogul, MDy

Abstract: Coincidence of the Eagle syndrome and diffuse idio- pathic skeletal hyperostosis can very rarely result with compression of the hypopharynx. The authors here described a very rare case of hypopharyngeal airway compression secondary to cervical osteo- phytes in a patient with coincidence of Eagle syndrome and diffuse

From the Ear, Nose and Throat Clinic; and yDepartment of Radiology, Medical Faculty, Ataturk University, Erzurum, Turkey. Received September 3, 2016. Accepted for publication September 30, 2016. Address correspondence and reprint requests to Dr Hayri Ogul, MD, Department of Radiology, Faculty of Medicine, Ataturk University, FIGURE 1. Multiplanar MDCT reconstruction image (A) reveals bilaterally 25240 Erzurum, Turkey; E-mail: [email protected] elongated styloid processes. Axial and sagittal MDCT scans (B and C) of the The authors report no conflicts of interest. cervical spine demonstrate anterior longitudinal ligament hypertrophy with Copyright # 2016 by Mutaz B. Habal, MD giant anterior osteophytes. Three-dimensional volume-rendered air-specific ISSN: 1049-2275 MDCT imaging shows the relationship between the hypopharyngeal air column DOI: 10.1097/SCS.0000000000003320 and the giant osteophytes (D). MDCT, multidetector computed tomography.

# 2017 Mutaz B. Habal, MD e129 Copyright © 2017 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.