Syndromes with Unusual Facies Alia Koch, DDS, MD a,b,*, Sidney Eisig, DDS a,b KEYWORDS  Syndrome  Facies  Malformations  Development  Prader-Willi syndrome  Cornelia de Lange syndrome  Fetal alcohol syndrome  Whistling face syndrome  Noonan syndrome

Cornelia de Lange syndrome

Key points  Syndrome is a clinical diagnosis.  Many craniofacial abnormalities include synophrys, long philtrum, and cleft palate.  Limb malformations are seen in these patients, along with toe fusion.  Developmental delay is common.

Genetics Multiple genes have been associated with this syndrome, including nipped-B-like protein (NIPBL) on chromosome 5, SMC1A, SMC3, and HDAC8 on the X chromosome. Most of these cases are secondary to spontaneous genetic mutations.

Clinical features Cornelia de Lange syndrome is a clinical diagnosis, based on signs and symptoms. Certain features are noted, including low birth weight, developmental delay, small stature, microcephaly, low hairline with synophrys, flat nasal bridge, long philtrum, low-set ears, widely spaced teeth, cleft palate, limb differences, excessive body hair, and partial fusion of the second and third toes. Children often have long eyelashes (Fig. 1). Cardiac abnormalities may also be present at birth. Gastrointestinal difficulties, including vomiting, diarrhea, and constipation, are common. Behavior issues may play a role in children as well, including self-injury and aggression. Patients may display behaviors similar to autism.

The authors have nothing to disclose. Hospital Dentistry, Oral and Maxillofacial Surgery, Columbia University College of Dental Medicine, New York, NY, USA b Hospital Dental Service, New York-Presbyterian/Columbia University Medical Center, 180 Fort Washington Avenue, New York, NY 10032, USA * Corresponding author. E-mail address: [email protected] a

Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 205–210 1061-3315/14/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cxom.2014.05.004

Differential diagnosis Whistling face syndrome Fetal alcohol syndrome

Treatment considerations for Oral and Maxillofacial Surgeons A thorough physical examination is important at birth to look for craniofacial abnormalities associated with this syndrome. A cleft palate, if present, should be noted, in order to plan for correction before speech development. Because of the multisystem involvement of this syndrome, including congenital cardiac defects, it is important to consult the patient’s primary care physician before any procedure with or without conscious sedation.

Prader-Willi syndrome Key points  Most patients inherit disease from paternal chromosome 15.  Patients have severe hypotonia and feeding difficulties in infancy.  Patients develop morbid obesity and diabetes.  Patients have hypogonadism with incomplete pubertal development.  These patients show learning disabilities and behavioral problems.

Genetics Prader-Willi syndrome is sporadically inherited from deletion or impaired expression of chromosome 15, specifically 15q11-13. Diagnosis is confirmed using DNA methylation or fluorescent in situ hybridization analysis. The incidence ranges from 1 in 10,000 to 1 in 20,000. There is equal distribution in male and female patients, as well as along differing ethnicities. In 70% of the cases, the abnormal gene is from a paternal inheritance; however, uniparental maternal disomy can lead to Prader-Willi syndrome in 25% of cases, with purely abnormal gene expression comprising 1% to 5% of the cases.

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Koch & Eisig obsessive-compulsive disorder (OCD) and oppositional behavior possibly secondary to hypothalamic dysregulation. Skin picking is a common manifestation of OCD. Patients with Prader-Willi have several dysmorphic features, including almond-shaped eyes; dolichocephaly; and small mouth, hands, and feet. The characteristic facial features may not be apparent at birth, but develop over time. Prosodic speech is common, secondary to a speech articulation defect. In addition, these patients show a global motor delay, as well as learning disabilities caused by a low intelligence quotient (Fig. 2). Differential diagnosis Craniopharyngioma Central nervous system depression Neonatal sepsis Myopathy Fragile X syndrome

Treatment considerations for Oral and Maxillofacial Surgeons These patients have numerous abnormalities, and are best served with a multidisciplinary approach. In oral and maxillofacial surgery, the patients are high risk when considering in-office surgical procedures and intravenous sedation. In addition to the behavior management skills required, attention needs to be directed toward airway management in these patients. Many are obese and produce a thick viscous saliva.

Fig. 1 (A, B) Facial appearance in Cornelia de Lange syndrome in this young boy. Note synophrys with a low hairline along with craniofacial anomalies including a flat nasal bridge and a long philtrum. (From Minor A, Marwan S, Hogue JS, et al. Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case. Gene 2014;537:2; with permission.)

Clinical features These patients typically show central infantile hypotonia with a poor suck at birth. The hypotonia is universal and can also lead to lethargy, a weak cry, and decreased movement. This condition leads to infant feeding difficulty, which causes an extreme drive to eat. Patients typically display morbid obesity, with short stature. The inability to feel satiated is secondary to hypothalamic abnormalities and causes patients to display food-seeking behavior, hoarding food, and eating of inedible objects. These patients develop sleep apnea and diabetes. It is common to see psychological disturbances, including

Fig. 2 This boy with Prader-Willi syndrome is obese, as is common in the disease process. Also note his small stature, small hands, and small feet. His eyes also have the characteristic almond shape. (From Jorde LB, Carey JC, Bamshad MJ, et al. Medical genetics. 3rd edition. Philadelphia: Mosby, An Imprint of Elsevier; 2003. p. 78.4.20.)

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Patients with Prader-Willi can also show apneic episodes and are hypotonic. A sleep study may be indicated in patients with Prader-Willi. These concerns need to be addressed before conscious sedation, and consideration of an operating room setting is advisable. Early use of growth hormone replacement in these patients can prevent the development of the facial dysmorphic features.

Fetal alcohol syndrome Key points  Syndrome associated with alcohol intake during pregnancy.  Variability associated with timing of alcohol ingestion, amount consumed, and duration of use.  Craniofacial abnormalities include smooth philtrum and thin vermilion.

Genetics Alcohol passes the placental barrier, causing damage to the developing central nervous system primarily but also causes changes in the facial form, learning disabilities, functional disabilities, and behavioral problems. At present, the pattern develops in the offspring of expectant women who consume large quantities of alcohol. The prevalence of fetal alcohol syndrome is 2 per 1000 live births. The variability of expression is thought to be related to the timing of alcohol ingestion relative to fetal development, the amount consumed, and the duration of alcohol use during pregnancy. Alcohol interferes with neural migration in the first trimester and damage to the hippocampus in the third trimester.

Clinical features Fetal alcohol syndrome affects numerous systems. These patients frequently have growth deficiency, in which height and weight are measured to be less than the tenth percentile. There are 3 distinctive facial characteristics that must be present to diagnose this syndrome: smooth philtrum, thin vermilion, small palpebral fissures. Having all three changes indicates abnormal brain development, although brain damage may be present without these signs. Alcohol can severely affect the central nervous system. Changes include microcephaly and structural changes in the brain. Neurologic symptoms include epilepsy, seizures, poor gait, neurosensory hearing loss, and impaired fine motor skills. Functional changes such as learning disabilities, poor academic achievement, poor memory, inattention, and low performance in an academic setting are all seen in this disease. Other craniofacial changes include epicanthal folds, poor nasal bridge support, and a short, upturned nose. Cardiac and renal systems can be affected as well. Atrial septal defects are rare, but have been seen. Hypoplastic, dysplastic, and aplastic kidneys have also been described. A multiteam approach is necessary to diagnose this syndrome. The following criteria are necessary to have a diagnosis of fetal alcohol syndrome: growth deficiency, all three facial features noted earlier, clinically significant central nervous system damage, and a history of prenatal alcohol use (Fig. 3).

Fig. 3 This young girl was born with fetal alcohol syndrome. She has a thin upper lip, with a smooth philtrum. She also has small palpebral fissures. (From Turnpenny PD, Ellard S. Emery’s elements of medical genetics. 14th edition. Philadelphia: Churchill Livingstone; 2011. Fig. 16.6; with permission.)

Differential diagnosis Noonan syndrome Williams syndrome Aarskog syndrome

Treatment considerations for Oral and Maxillofacial Surgeons When an infant is born and concern for fetal alcohol syndrome exists, a full physical examination is necessary to evaluate the changes in the facial stigmata. Furthermore, a close examination is necessary to rule out diagnosis of a cleft lip and/or palate. These patients need a multidisciplinary approach, and referral to a craniofacial team to evaluate and treat the syndrome is appropriate. Throughout life, the patient’s facial stigmata should be evaluated for possible orthognathic surgery. In an office setting, concerns for surgical procedures and conscious sedation need to be discussed with patients’ primary care physicians and specialists. Primary concerns include metabolism of medications through the liver and the renal system. Appropriate dosing in these patients should be done in accordance with blood tests evaluating renal and liver function.

Whistling face syndrome

Key points  Genetic disorder with recessive and dominant inheritance patterns.  Patients show craniofacial and orthopedic changes.  Syndrome defined as congenital myopathy.

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Genetics This syndrome is either autosomal dominant or autosomal recessive, based on the type of expression of disease. The phenotypic changes seen in this syndrome are caused by mutations in the embryonic myosin heavy chain (MYH3). There is no sex or ethnic predilection. This disease has very few data, because only 65 patients have been reported in literature.

Clinical features This syndrome is considered a myopathy. There are several clinical features associated with whistling face syndrome. Patients have drooping upper eyelids, low-set ears, a long philtrum, strabismus, and difficulty walking. Patients show

Koch & Eisig microstomia, puckered lips, small tongue, a soft palate with limited movement, and dimpling over the chin in a Y or H shape. Other associated craniofacial changes include small nose; micrognathia; choanal atresia; hearing loss; flat midface; and a masklike, rigid face. A webbed neck is common as well. Patients have difficulty swallowing secondary to the mouth deformities. Multiple congenital joint contractures are defined as part of the syndrome, showing a type 2A distal arthrogryposis with ulnar deviation of the fingers. Patients show camptodactyly, as well. Bilateral talipes equinovarus and kyphoscoliosis are commonly seen. Gastroesophageal reflux is common in infancy (Fig. 4). Diagnosis is made when at least 2 of the major clinical manifestations of distal arthrogryposis are found with

Fig. 4 (A) Whistling face syndrome: note the low-set ears and the neck contractures. (B) A patient with arthrogryposis of the hand with contractures as seen in whistling face syndrome. (C) Patients with whistling face syndrome show an abnormally crowded dentition. (D) Numerous signs of whistling face syndrome. Note the webbed neck, low-set ears, microstomia, downslanting eyes, and mask facies. (Courtesy of D. DeLuke, DDS, MBA, Richmond, VA.)

Syndromes with Unusual Facies craniofacial changes. Prenatal diagnosis can be made by ultrasonography at 20 weeks and by genetic testing. Differential diagnosis Arthrogryposis Cornelia de Lange syndrome Trisomy 18

Treatment considerations for Oral and Maxillofacial Surgeons Early intervention is necessary in this disease in order to minimize the effect of the myopathy on growth and development. Because muscle physiology is abnormal, endotracheal intubations and intravenous line placement can be difficult. It is prudent to conduct awake fiberoptic intubations in patients with the syndrome. These patients are at risk for developing malignant hyperthermia. After surgery, patients are at risk for respiratory failure secondary to myopathy and skeletal changes. Tracheostomy should be considered for those patients with severe narrowing of the upper airway.

Noonan syndrome

Key points  Autosomal dominant inheritance with mutation in the RAS mitogen-activated protein kinase pathway.  Clinical examination for characteristic changes is necessary for diagnosis.  Patients with disease are high risk for congenital cardiac disease.  This syndrome affects multiple physiologic systems, including renal, cardiac, hematologic, and endocrine.

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Genetics Noonan syndrome has an autosomal dominant inheritance pattern with an incidence of 1 in 1000 to 1 in 2500. Male and female incidence is equal. Genetics of the disease are not well understood, although the genes of the RAS mitogen-activated protein kinase (MAPK) pathway have been found to cause Noonan syndrome. More specifically, mutations in the protein tyrosine phosphatase nonreceptor type 11 gene are now identified. There have also been numerous other genes identified; however, the diagnosis still relies on a clinical examination.

Clinical features A clinical examination is essential for the diagnosis of Noonan syndrome. After birth, these patients show early feeding difficulties, webbed neck, low posterior hairline, ptosis, hypertelorism, low-set posteriorly rotated ears, and downslanting palpebral fissures (Fig. 5). Learning disabilities are a concern for these patients as well. There are several different systems affected by the disease. A solitary kidney, duplicate collecting system, and renal pelvis dilatation are common findings in the renal system in approximately 10% of the Noonan syndrome population. Eighty percent of male patients have cryptorchidism. Male patients also have delayed puberty and infertility, secondary to Leydig and Sertoli cell dysfunction. On hematology, these patients typically have thrombocytopenia, coagulation factor deficiencies, and platelet dysfunction. Factor 11 deficiency is the most common. Short stature is common, affecting from 50% to 70% of individuals. The cause is not clear. Growth hormone therapy has been shown to be effective. These patients have associated cardiac defects, including pulmonary valve stenosis, and are at increased risk of developing hypertrophic cardiomyopathy. Echocardiography is

Fig. 5 Young boy with Noonan syndrome. The patient has hypertelorism with downslanting palpebral fissures. His ears are posteriorly rotated and low set. (From Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 2011;25(1):161e79; with permission.)

210 essential to monitor heart function and cardiac wall thickness before any treatment or surgeries. The RAS-MAPK pathway is associated with oncogenesis and, as such, patients with Noonan syndrome are at higher risk for leukemia and solid tumors compared with the general population. Differential diagnosis Turner syndrome Williams syndrome Aarskog syndrome

Treatment considerations for Oral and Maxillofacial Surgeons Noonan syndrome is a multisystem disease, thus requiring appropriate management in all its aspects. The diagnosis and management of hematologic disorders is important in any surgical procedures, and appropriate laboratory tests should be ordered to prevent any complications after surgery. Appropriate laboratory tests include a complete blood count with platelet count, prothrombin time and International Normalized Ratio, and activated partial thromboplastin time. Patients with Noonan syndrome have numerous congenital cardiac malformations and, secondary to the use of growth hormone, may also have developed ventricular wall thickening. In the management of these patients in the oral and maxillofacial surgery office, it is of great importance to discuss with the patient’s cardiologist any future surgical procedures that may or may not include conscious sedation. Renal function should be assessed and medications appropriately dosed. Besides medications, any intravenous fluid therapy for patients undergoing conscious sedation needs to be appropriately dosed based on kidney function.

Koch & Eisig In addition, because these patients have numerous cardiac and renal anomalies, it is important to review the antibiotic premedication guidelines to ensure that premedication is dosed appropriately when deemed necessary.

Further readings Astley SJ, Clarren SK. A case definition and photographic screening tool for the facial phenotype of fetal alcohol syndrome. J Pediatr 1996; 129:33e41. Benarroch F, Hirsch HJ, Genstil L, et al. Prader-Willi syndrome: medical prevention and behavioral challenges. Child Adolesc Psychiatr Clin N Am 2007;16:695e708. CdLS Foundation Website. Cornelia de Lange syndrome Foundation. Chacko E, Graber E, Regelmann MO, et al. Update on Turner and Noonan syndromes. Endocrinol Metab Clin North Am 2012;41:713e34. Chen H. Freeman-Sheldon Syndrome. In: Chen H, editor. Atlas of genetic diagnosis and counseling. US: Springer; 2012. p. 883e9. Church MW, Abel EL. Fetal alcohol syndrome hearing, speech, language, and vestibular disorders. Obstet Gynecol Clin North Am 1998;25:85e97. Clarren S, Alvord EC Jr, Sumi SM, et al. Brain malformations related to prenatal exposure to ethanol. J Pediatr 1978;92:64e7. Coles C, Brown RT, Smith IE, et al. Effects of prenatal alcohol exposure at school age. Neurotoxicol Teratol 1991;13:357e67. Driscoll D, Miller J, Schwartz S, et al. Prader-Willi syndrome. NCBI Bookshelf; 2012. Institute of Medicine, Stratton K, Howe C, Battaglia F, et al. Fetal alcohol syndrome: diagnosis, epidemiology, prevention, and treatment. National Academy Press. Landgraf M, Nothacker M, Kopp IB, et al. The diagnosis of fetal alcohol syndrome. Dtsch Arztebl Int 2013;42:703e10. Nargozian C. The difficult airway in the pediatric patient with craniofacial anomaly. Anesthesiol Clin North America 1998;16:839e52. Streissguth A, Aase JM, Clarren SK, et al. Fetal alcohol syndrome in adolescents and adults. JAMA 1991;265:1961e7. Toriello H. Role of the dysmorphologic evaluation in the child with developmental delay. Pediatr Clin North Am 2008;55:1085e98.

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