Syndromes of orofacial region mine

This is a very comprehensive seminar on Syndromes of Orofacial region, easy classification and easy understanding.
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1. Syndromes of Orofacial Region Resource faculties: Dr. Jyotsna Rimal Additional Prof. and HOD Dr. Iccha Kumar Maharjan Associate Prof. Dr. Sushma Pandey ( Dhakal ) Associate Prof. Presenter : Abhinaya Luitel JR- II Department of Oral Medicine and Radiology 1

2. Syndrome and symptom Common terminologies Cause of syndrome Clinical approach to syndrome Syndrome with deficient mandible Syndrome with deficient maxilla Syndrome with connective tissue deficiency Syndrome with congenital skin anomaly Syndrome which become apparent after infancy Syndromes associated with fibro-osseous lesions of jaws C O N T E N T S 2

3. Syndrome associated with red and white lesions of oral cavity Syndrome associated with facial nerve palsy Syndrome associated with mucopolysachharodosis Syndromes primarily associated with cleft lip/palate Miscellaneous syndromes Genetic services, counselling and screening Genetic clinic at BPKIHS Summary Conclusion MCQs References C O N T E N T S 3

4. Syndrome Recognized pattern of clinical abnormalities that have a single cause. (Rosalind Smyth, Textbook of Pediatrics, 2003) Combining its two Greek roots ( syn - + dramein ),  syndrome  means " running together “ * Merriam-Webster Medical Dictionary 4

5. Symptom vs Syndrome 5

6. Terminologies MALFORMATION: It is the defect due to localized error of morphogenesis resulting in an abnormal shape or structure with the interference in function. Eg : Cleft lip and palate. DEFORMATION: Arises not from an error in embryological development but normal fetal growth is restricted. Eg : Low set ears ANOMALY: It is the deviation from normal same as malformation but without interference in function. Eg . Peg shaped lateral, Enamel hypoplasia. 6

7. ANOMALAD: Recognized pattern of congenital abnormalities that may have several different causes. Eg : Robin Anomalad (micrognathia, cleft palate, posteriorly displaced tongue) may be a feature of Stickler’s syndrome. ASSOCIATION : Combination of congenital abnormalities that occur together at a frequency greater than by chance but do not appear to recur in the family. Eg : CREST, SHORT SEQUENCE: Series of malformation that arise secondary to one specific developmental incident. Eg : Robins Sequence 7

8. AUTOSOMAL DOMINANT (AD): Inheritance of the abnormal gene from only one parent can cause the disease. AUTOSOMAL RECESSIVE (AR):  Inheritance of two copies of an abnormal gene must be present in order for the disease or trait to develop. 8

9. X-LINKED DOMINANT (XD):  Gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent. X-LINKED RECESSIVE (XR): Inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation 9

10. Cause of syndrome When one or more chromosomes are missing or   mutated , or if extra chromosomes are present, the proteins may not get made, made incorrectly , or too many may be made.  Can cause abnormal development and growth and result in a   syndrome .  Sometimes these abnormal genes or chromosomes are passed down from a parent, and sometimes they occur spontaneously without reason Michigan Medicine, 1500 E. Medical Center Drive Ann Arbor, MI 48109 734-936-4000 © copyright 2017 Regents of the University of Michigan 10

11. Clinical approach to diagnosis of syndrome Clinical diagnosis (History + Clinical signs + knowledge of pattern of abnormalities) Rare: Laboratory examinations Yes: Radiology Cytogenetics Relatively common: General population Single palmar crease Partial syndactyly of 2 nd and 3 rd toe MINOR clinical signs Rare: General population Cleft lip/ palate Polydactyly MAJOR clinical signs Management: Communication skills and communication aids Consent and autonomy Access to care: comfort and positioning Physical interventions: Restrains Multidisciplinary approach Regular follow up: Childhood to Adulthood. 11

12. Syndromes with Deficient Mandible 12

13. Treacher Collins syndrome (Mandibulofacial dysostosis , Franceschetti- Zwalen -Klein syndrome, Treacher Collins-Franceschetti syndrome) Edward Treacher Collins: Opthalmologist , 1900 Incidence: 1 in 25000 to 50000 Inheritance : AD Mutation : TCOF1 (AD), POLR1C (AD, AR)  or  POLR1D (AR) 13

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15. Paranasal sinus and mastoid air spaces: small or unapparent One third: palatal cleft Occasional: Hypoplastic tooth, tooth agenesis, ectopic eruptions, mental retardation, parotid aplasia, skeletal malformations, cardiac anomalies. Diagnosis: Clinical features, Imaging of craniofacial structures, molecular genetic testing Prenatal (if suspected): Amniocentesis, Chronic villus sampling 15

16. Management: Multidisciplinary approach Pediatricians, Otolaryngologists, Oral physicians, Pedodontist , Orthodontist, Prosthodontist, Oral surgeons, Plastic surgeon, Speech therapist, Audiologists, Ophthalmologists, Psychologists, Geneticists. Esthetics: Reconstructive surgery Surgical closure of clefts Orthodontic treatment Prosthesis 16

17. Robin Sequence (Pierre Robin Syndrome, Robin Anomalad ) Lannelongue and Menard: 1891 1 per 8500 live births. New De Novo genetic changes but when inherited AD Mutation : S0X9 17

18. Micrognathia Glossoptosis Cleft palate 18

19. Labored inspirational breathing Cyanotic episodes in supine position Occasional: cardiac defects, ocular abnormalities, mental retardation, ear malformation Diagnosis: Clinical features, Imaging of craniofacial structures, molecular genetic testing Prenatal: Ultrasonography 19

20. Management: Multidisciplinary approach Pediatricians, Otolaryngologists, Oral physicians, Pedodontist , Orthodontist, Oral surgeons, Plastic surgeon, Speech therapist, Psychologists, Geneticists. Infancy: breathing support and feeding assistance Surgical cleft closure Orthodontic treatment Cardiac defects: Infective endocarditis prophylaxis during invasive dental procedures 20

21. Syndromes with Deficient Maxilla 21

22. Crouzon Syndrome (Craniofacial Dysostosis , Crouzon Disease, Apert Crouzon Syndrome) Octave Crouzon: French physician, 1912 Incidence: 1 per 60000 live birth Inheritance : AD Mutation : Fibroblast growth factor receptors (FGFR) 2 22

23. Craniosynostosis Head: Brachycephaly, Scalocephaly , Trigonocephaly, Cloverleaf deformity Proptosis: exposure keratitis, conjunctivitis Frontal bossing Midface hypoplasia 23

24. Radiograph: “Beaten silver” appearance, Digital impressions Parrot shaped prominence of nose Narrow maxillary arch, crowding of maxillary teeth Rare: ocular malformations, cleft palate, hearing loss Diagnosis: Clinical features, Imaging of craniofacial structures, molecular genetic testing 24

25.  Pediatricians, Neurosurgeons, Plastic surgeons, Otolaryngologists, Audiologists, Ophthalmologists, Dental specialists, Geneticists Surgery: create and ensure that there is enough room within the skull for the developing brain to grow; to relieve intracranial pressure (if present) Surgical correction of maxillofacial deficiency Orthodontic treatment Management: Multidisciplinary approach 25

26. Apert Syndrome ( Acrocephalosyndactyly I, syndactylic oxycephaly) Eugene Apert:1906 1 in 65000 live birth. Inheritance : AD Mutation : FGFR 2 (Pro253Arg, Ser252Trp) 26

27. Craniosynostosis Midface hypoplasia Syndactyly Frontal flattening Hypertelorism Depressed nasal bridge Exophthalmos Mitten like syndactyly Valgus deformity Pinky Hallux Varus Acrocephaly 27

28. Constricted palate Narrow arch Crowding of teeth Short stature Mental retardation Rare: cleft palate, cardiac malformations, delayed eruption of teeth Diagnosis: Clinical features, Imaging of craniofacial structures, molecular genetic testing Prenatal: fetoscopy , ultrasonography 28

29. Pediatricians, Surgeons, Physician, Orthopedicians , Otorhinolaryngologist , Cardiologists, Dental specialist, Geneticist, Psychologist  Early surgery (within 2 to 4 months after birth): correct craniosynostosis Orthognathic surgery Orthodontic treatment Management: Multidisciplinary approach 29

30. Down Syndrome (Trisomy 21, Mongolism) John Langdon Down : English Physician, 1862 Not inherited Incidence: 1 in 1000 to 1 in 1100 live births. Robertsanian translocation: Female (47, XX, +21) Male (47, XY, +21) Mosaicism: Some cells have trisomy 21 while some are normal 30

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32. Intellectual disability Irregular speech Autism Epileptic seizure Strabismus Keratoconus (cone shaped cornea) Atrioventicular septal defect High risk: testicular cancer, leukemia Oral manifestations: Gingivitis Periodontitis Greater resistance to tooth decay Macroglossia Bruxism Hypoplastic maxilla Narrow arch Malocclusion Delayed exfoliation and eruption of teeth 32

33. Diagnosis: Clinical features, Imaging of craniofacial structures, molecular genetic testing Prenatal: Amniocentesis, Chronic Villous Sampling, Ultrasonography 33

34. Cardiovascular surgery Hearing Aids Speech Therapy Augmentative and alternative communication methods Tonsillectomy Oral hygiene maintenance Orthognathic surgery Orthodontic treatment Management: Multidisciplinary approach Pediatricians, Physicians, Surgeons, Otorhinolaryngologist , Speech therapist, Dental specialist, Psycologist , Geneticist 34

35. Cleidocranial Dysplasia (Cleidocranial Dysostosis , Marie- Sainton Syndrome) Martin: 1765 Marie and Sainton : 1898 (Description) 1 in 1000000 live births. Inheritance : AD Mutation : Cbfa1 35

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37. Frontal, parietal, occipital bossing Hypoplastic maxilla High arched palate Hypoplasia or aplasia of paranasal sinus Delayed exfoliation of primary tooth Delayed eruption of permanent tooth Malocclusion Diagnosis: Clinical features, Imaging of craniofacial structures, Molecular genetics 37

38. Management: Multidisciplinary approach Pediatricians, Surgeons, Orthopedicians , Dental specialist, Otorhinolaryngologist , Psycologist , Geneticist Orthognathic surgery Removal of deciduous and supernumerary tooth Surgical exposure and orthodontic guidance of permanent tooth ENT consultation 38

39. Syndromes of Connective Tissue Deficiency 39

40. Ehlers-Danlos Syndrome (Cutis Hyperelastica , Dermatorrehxis ) Edvard Ehlers: 1901, recognized the condition as a distinct entity. Henri-Alexandre Danlos: 1908, skin extensibility and fragility were the cardinal features. Incidence: 1 in 5000-10000 live births. 40

41. Villefranche classification Berlin classification Protein Mutation Inheritance  Classical type I/ II V collagen COL5A1, COL5A2 AD Hypermobility type III Unknown TNXB AD Vascular type IV III collagen COL3A1 AD kyphoscoliosis type VI Lysyl hydroxylase PLOD1 AR Arthrochalasia type VIIA/ B I collagen COL1A1, COL1A2 AD Dermatosparaxis type VII C N-proteinase ADAMTS2 AR 41

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43. Velvety skin Easy bruising Poor wound healing Joint sublxation / Dislocation Early onset arthritis Blue sclera Mitral valve prolapse Oral manifestations Vulnerable oral mucosa to injury Poor suture retention Conical incisor Rhizomicry Pulpal calcification Supple tongue High arched palate Early onset Periodontitis (VIII) Diagnosis: clinical examination, skin biopsy, Beighton scale, CT, MRI, Echocardiography, Molecular genetics 43

44. Pediatricians, orthopedists, Dermatologist, Rheumatologist, Cardiologist, Surgeons, Dental specialists, Psychlogist , Geneticist Prevention of trauma to joint Avoiding unnecessary surgical exposure Avoid incidental injury to skin and mucosa Infective endocarditis prophylaxis before invasive dental procedures. Management: Multidisciplinary approach 44

45. Marfan syndrome (Arachnodactyly) Antoine Marfan : French Doctor, 1896 Incidence: 1 in 5000-10000 live births. Inheritance : AD Mutation : Fibrillin 1 (FBN1) 45

46. Dolicocephaly Ectopia lentis (dislocated eye lens) Myopia Dolichostenomelia Arachnodactyly Pectus excavatum/ Carinatum Mitral valve prolapse/ Aortic aneurysm Scoliosis Pes planus 46

47. Oral manifestations: Malar hypoplasia Prognathic mandible High arched palate Malocclusion Diagnosis: clinical examination, complete skeletal examination, echocardiography, molecular genetics Ghent Nosology 2010: Aortic aneurysm, eye lens dislocation, family history of Marfan syndrome 47

48. Geneticists, Surgeons, Cardiologists, Dental specialists, Ophthalmologists, Orthopedists Orthognathic surgery Orthodontic treatment Infective endocarditis prophylaxis before invasive procedure Management: Multidisciplinary approach 48

49. Ellis-van Creveld Syndrome (Chondroectodermal Dysplasia, Mesoectodermal Dysplasia) Richard W.B. Ellis,Edinburgh and Simon van Creveld , Amsterdam: late 1930 Incidence: 1 in 60000-200000 live births. Inheritance : AR Mutation : EVC2 49

50. Atrial septal defect Cryptoorchidism (Males) Diagnosis: Clinical features, Skeletal examination, Imaging modalities, Molecular genetics 50

51. Pediatricians, Surgeons, Cardiologists, Dental specialist, Pulmonologists, Orthopedists, Urologists Surgical correction of soft tissue malformation Orthodontic treatment Prosthesis for missing teeth Infective endocarditis prophylaxis for invasive procedures Management: Multidisciplinary approach 51

52. Syndromes of Congenital Skin Abnormality 52

53. Hypohidrotic Ectodermal Dysplasia (Anhidrotic Ectodermal Dysplasia, Christ-Siemens-Touraine Syndrome) Weech: 1929, ectodermal dysplasia Josef Christ: German dentist and physician, identify the condition (1930) Hermann Werner Siemens: German dermatologist, identified its pathological characteristics (1930) Albert Touraine: French dermatologist, noted and identified additional characteristics (1930) 53

54. Inheritance : XR Mutation : EDA Incidence: 7 per 10000 live births 54

55. Hypohydrosis Hypotrichosis Hypodontia Saddle nose Frontal bossing Periorbital hyperpigmentation and wrinkling Hypoplasia/ aplasia of eccrine glands Opthalmic / respiratory infections Pruritis Eczema Unexplained high fever 55

56. Oral manifestations: Majority of primary and permanent teeth absent Teeth present are conical and microdontic Alveolar ridge fails to form properly Everted lips Diagnosis: Clinical examination (classic triad), Skin biopsy, pilocarpine iontophoresis, Radiographic adjuncts, molecular genetics 56

57.  Pediatricians, Physicians, Dermatologists, Dental specialists, Otolaryngologists, Allergists, Psychologist, Geneticist Removal of very few remaining teeth followed by complete prosthesis Partial denture prosthesis if feasible Orthodontic treatment if possible Management: Multidisciplinary approach 57

58. Sturge Weber Angiomatosis ( Encephalofacial angiomatosis , Encephalotrigeminal angiomatosis , Leptomeningeal angiomatosis , Sturge- Kalischer -Weber syndrome, Sturge-Weber- Krabbe syndrome, Sturge-Weber phakomatosis ) William Allen Sturge and Frederick Parkes Weber: 19 th and early 20 th century Incidence: 1 in 20000 to 50000 live birth. Inheritance : none, Somatic mutation (Mosaicism) Mutation: GNAQ 58

59. Type I: Skin + Neorological symptoms Type II: Skin symptoms + Glaucoma Type III: Neurological symptoms 59

60. Diagnosis: clinical features, neuroimaging, EEG, Molecular genetics 60

61. Pediatricians, Neurologists, Neurosurgeons, Vascular surgeons, Maxillofacial surgeons, Dermatologists, Ophthalmologists, Psychologists, geneticists  Pulse dye laser therapy Correction of Malocclusion if any Invasive procedures on affected side should be avoided as possible Management: Multidisciplinary approach 61

62. Peutz-Jeghers Syndrome (Polyposis, Hamartomatous Intestinal, Polyps and Spots Syndrome) Jan Peutz: 1921, first reported case Harold Joseph Jeghers: 1949, Formalized to syndrome Andre J. Bruwer: 1954, Introduced a syndrome Incidence: 1 in 8000-200000 live births. Inheritance : AD Mutation: STK11 62

63. Skin discoloration around eyes, nostrils, perianal areas. Diagnosis: Intestinal polyps, Melanin spots, positive family history (2 of 3) Molecular genetics 63

64. Management Routine Endoscopy Prevention of intestinal obstruction and cancer Perioral pigmentation can be removed with laser if unesthetic Genetic counselling 64

65. Syndromes that become apparent after infancy 65

66. Gardner Syndrome (Intestinal polyposis, Osteomatosis intestinal polyposis syndrome) Gardner: 1951 Inheritance: 1 per 7500 live births. Inheritance : AD Mutation : Adenomatous Polyposis Coil (APC) suppressor gene 66

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68. Oral manifestations: Multiple odontomes Multiple impacted supernumerary tooth Generalized failure of tooth to erupt Diagnosis: sigmoidoscopy, colonoscopy, Imaging modalities, molecular genetics 68

69. Physicians, Surgeons, Gastroenterologist, Maxillofacial surgeons, Dental specialist, Psychologists, Geneticists Removal of osteomas for cosmetic and functional reasons Surgical removal of impacted supernumerary tooth Surgical removal of multiple odontomes Prosthesis for missing teeth Management: Multidisciplinary approach 69

70. Nevoid Basal Cell Carcinoma Syndrome ( Gorlin Goltz syndrome, Gorlin syndrome, Basal cell Nevus syndrome, Jaw cyst-basal cell nevus-bifid rib syndrome, Hermans -Herzberg phakomatosis ) Robert Gorlin and Robert Goltz: 1960 Incidence: 1 per 57000 live births. Inheritance : AD Mutation : PTCH1 70

71. 71 Sprengel deformity

72. Oral manisfestations Multiple KCOT Displaced permanent tooth Ectopic eruption of tooth Malocclusion 72

73. Diagnosis Major criteria: >2 basal cell skin cancer Dural calcification Jaw bone cyst 3 or more pits on palms and soles Parent or sibling with NBCCS Minor criteria: Medulloblastoma Large forehead Polydactyly Bifid ribs Eye problems ( hypertelorism , cataract) Fibroma of ovary or heart Abdominal cyst 2 major+1 minor or 1 major+3 minor 73

74. Pediatricians, Dermatologists, Oral surgeons, Dental specialist, Cardiologists, Ophthalmologists, Plastic surgeons, Psychologist, Geneticist Surgical enucleation of multiple cysts Extraction of hopeless tooth Extraction of ectopically erupted tooth Orthodontic correction Prosthesis for missing teeth when necessary Management: Multidisciplinary approach 74

75. Papillon - Lafevre Syndrome ( Keratoris Palmoplantaris with Periodontopathia , Periodontoclasia in childhood) MM Papillon and Paul Lafevre Incidence: 1-4 cases per million live births. Inheritance : AR Mutation : CTSC 75

76. Dystrophic nails Pyogenic skin infections (furuncles) Hyperhydrosis 76

77. Severe inflammation and degeneration of the structures surrounding and supporting the teeth (periodontium). The primary (deciduous) teeth frequently become loose and fall out by about age 5. Most of the permanent teeth may also be lost by approximately age 17 Diagnosis: clinical examinations, radiographs, urinanalysis , molecular genetics 77

78. Pediatricians, Dermatologist, Oral physiscians , Oral surgeons, Pedodontist , Periodontist, Prosthodontist, Psychologist, Geneticist Periodontal therapy Antibiotic coverage Extraction of hopeless teeth Prosthesis for missing teeth Management: Multidisciplinary approach 78

79. Plummer- Vinson Syndrome ( Sideropenic dysphagia, Paterson’s syndrome, Paterson- Brown-Kelly syndrome) Henry Plummer, Chicago: 1911 and Porter Vinson, Philadelphia: 1919 Donald Ross Paterson and Adam Brown Kelly published independently of each other in London in 1919 Incidence: 1-16 per 100 Genetic factors, Nutritional deficiencies: possible causes Affects middle aged women 79

80. Iron deficiency anemia (microcytic, hypochromic) Dysphagia Facial palor Fatigue weakness Schatzki ring   80

81. Oral manifestations: Angular cheilitis Atrophic oral mucosa Atrophic glossitis Burning tongue Diagnosis: Clinical features, CBC (microcytic hypochromic anemia), Low serum ferritin level, barium swallow (esophageal webs) 81

82. Management: Multidisciplinary approach Physicians, Surgeons, Dental Specialists Oral Iron supplement Non abrasive diet and use of bland Topical anesthetics application Prevention of superficial fungal infection 82

83. Hereditary hemorrhagic Telangiectasia, HHT (Osler-Weber Rendu syndrome,Rendu -Osler-Weber syndrome)  Henry Gawen Sutton: 1864 (first described) Henri Jules Louis Marie Rendu: 1896 (differentiated Hemophilia )  William Osler connected the disease’s presence in families  Frederick Parkes Weber: 1907 (case series) 1909 83

84. Incidence: 1 in 10000 live births. Inheritance : AD Mutation :  ACVRL1, ENG, and   SMAD4 84

85. HHT1: A-V malformation of brain and lung HHT2: A-V malformation of liver HHT3 HHT4 HHT5: Juvenile polyps in colon Specific location unknown 85

86. A-V malformations in lung, brain, spinal cord, liver Dyspnea, hemoptysis, cyanosis, polycythemia vera Vertigo Portal hypertension, biliary disease Hyperdynamic circulation 86

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88. Management: Multidisciplinary Approach Pediatricians, Neurophysicians, Neurosurgeons, Physicians, Pulmonologist, Cardiologist, Hepato-Biliary specialist, Gastroenterologist, Dental specialist, Psychologist, Geneticist Improvement of systemic condition is emphasized upon Preventive measures in oral care: avoiding trauma, soft bland diet Infective endocarditis prophylaxis for invasive dental procedures. 88

89. Syndromes associated with Fibro-osseous Lesions of Jaws 89

90. Jaffe-Lichtenstein syndrome Dr. Lichtenstein: 1938 and in 1942 by Drs. Lichtenstein and Jaffe Incidence: 1 in 200000 live births. Inheritance : somatic mutation (not inherited) Mutation : GNAS1 90

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92. McCune Albright syndrome (Albright syndrome, osteitis fibrosa disseminate) Donovan James McCune and Fuller Albright: 1937 Incidence: 1 in 100000 live births. Inheritance : somatic mutation (not inherited) Mutation : GNAS1 92

93. Endocrinopathies: Precocious puberty (gonadotrophins) Hyperthyroidism (thyroid) Macrocephaly/ acromegaly (growth) Cushing syndrome (cortisol) 93

94. Mazabraud syndrome Mazabraud : 1967 Incidence: less than 1 per 1000000 live births Inheritance : somatic mutation (not inherited) Mutation : GNAS1 (relation between fibrous dysplasia and myxoma is still unclear) 94

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96. Oral manifestations: Facial asymmetry Uneven jaws Misaligned/ displaced teeth Other manifestations: Frontal bossing Bulging eyes Hearing loss Vision impairment Bone pain Pathologic fracture Diagnosis: Clinical features, CT, MRI, Calcium, Phosphorus, Alkaline phosphatase, Bone biopsy, Endocrinal evaluation, molecular genetics 96

97. Management: Multidisciplinary Approach  Pediatricians, Orthopedists, Endocrinologists, Dermatologists, Dental specialists, Psychologist, Geneticist Wait and watch: Decreases after puberty Bony contouring of the lesion (esthetic/ functional disturbances) Orthodontic correction if required 97

98. Noonan Syndrome ( Female pseudo-Turner syndrome, male Turner syndrome) Noonan and Ehmke: 1963 Incidence: 1 in 1000-2500 live births. Inheritance : AD Mutation : PTPN11  (50%),  SOS1  (10-13%),  RAF1 (5%),  RIT1  (5%), and  KRAS  (less than 5%) 98

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100. Congenital heart defects Malformations of blood and lymph vessels Blood clotting and platelet deficiencies Attention issues Intellectual disability Urine (fishy smell, trimethylaminuria) Oral manifestations: Distortion of alveolar ridges Tooth displacement Failure of eruption Impaired mastication Speech difficulty Diagnosis: Clinical features, Radiographic modalities, Echocardiography, Routine and special blood investigations, urinanalysis , Molecular genetics Prenatal: Ultrasonography, 100

101. Pediatricians, Cardiologists, Hematologists, Endocrinologists, Dental specialists, Psychologist, Geneticist Wait and watch: Puberty Surgical intervention and curettage after hematological consultation Orthodontic correction if needed Extraction of hopeless teeth Prosthetic replacement for missing teeth Management: Multidisciplinary Approach 101

102. Syndromes associated with Red and white lesions of oral cavity 102

103. Grinspan Syndrome Grinspan : 1963 observed. Grupper & Avul : 1965 confirmed and defined this complex as " Grinspan's syndrome” Incidence: 10% 103

104. Hypertension Diabetes mellitus Lichen planus Diagnosis 104

105. It is likely that Grinspans’s syndrome represents a drug induced disorder 105

106. Management: Multidisciplinary approach Physicians, Endocrinologist, Dermatologist, Dental Specialist Try to identify the causative agent Treatment for Oral lichen planus/ Lichenoid reaction to be initiated Prednisone 5 mg tablets as mouth rinse 3 times daily, Benzydamine hydrochloride 0.15% oral rinse 3 times daily Oral multivitamin with antioxidant 106

107. Syndromes associated with Facial nerve Palsy 107

108. Ramsay Hunt syndrome James Ramsay Hunt: 1907 Incidence: 0.3 to 18% Cause : Varicella Zoster Virus (VZV) In cases of Ramsay Hunt syndrome, previously inactive (dormant) varicella-zoster virus is reactivated in geniculate ganglion and spreads to affect the facial nerve. 108

109. Ramsay Hunt syndrome type 1: Ramsay Hunt cerebellar syndrome, cerebellar degeneration which involves myoclonic epilepsy, progressive ataxia, tremor, and a dementing process. Ramsay Hunt syndrome type 2 Ramsay Hunt syndrome type 3: Occupationally induced neuropathy of the deep palmar branch of the ulnar nerve. It is also called  Hunt's disease  or  Artisan's palsy 109

110. Diagnosis: Clinical features 110

111. Management Acyclovir 800mg five times/ day (5-7days) Prednisolone 1mg/Kg body weight tapered over a period of 21 days Anesthetic: lignocaine gelly 2% Incase of neuralgic pain: Carbamazepine 100mg HS, increase upto 200 mg TDS Gabapentin: 300 mg HS and increase upto 300mg TDS Eye drops: Tear plus (4-5times/day) 111

112. Melkersson –Rosenthal syndrome ( Miescher - Melkersson -Rosenthal syndrome) Ernst Melkersson and Curt Rosenthal Incidence: 8 per 10000 people. The cause is unknown but genetic predisposition is under study 112

113. Diagnosis: clinical features, Biopsy of lip 113

114. Management Most signs and symptoms resolve without treatment but episodes may occur more often and last longer if the condition is not treated. Treatment may include corticosteroid injections, nonsteroidal anti-inflammatory agents and antibiotics. Surgery and/or radiation are sometimes recommended to reduce abnormally swollen lips. 114

115. Syndromes associated with Mucopolysaccharodosis 115

116. Hurler Syndrome ( Mucopolysaccharidosis I, Gargoylism ) Dr. Gertrude Hurler: 1919 Incidence: 1 per 100000 live births. Inheritance : AR Mutation:  IUDA, deficiency of the enzyme alpha-L- iduronidase 116

117. Progressive mental retardation Organomegaly Poor growth Joint stiffness Hydrocephalus Aortic Regurgitation 117

118. Oral manifestations: Shortening & broadening of mandible with prominent gonian Macroglossia Increased distance from ramus to ramus, spacing of teeth Delayed tooth eruption Gingival hyperplasia Diagnosis: clinical features, Urinanalysis , Enzyme assay, molecular genetics Prenatal: Amniocentesis, Chronic Villous sampling 118

119. Management Poor prognosis Patient dies by the age of 10 years due to obstructive airway disease and cardiac complications Laronidase , an enzyme replacement therapy (FDA, 2003) is the first treatment approved. 119

120. Hunters Syndrome ( Mucopolysachharodosis II, Iduronate 2-sulfatase deficiency) Charles A Hunter: 1917 Incidence: 1.3 per 100000 live births. Inheritance : XR Mutation : IDS, eliminates function of Iduronate 2-sulfatase 120

121. Diagnosis: Clinical features, Enzyme assay, Urianalysis , Molecular genetics Prenatal: Amniocentesis, Chronic villous sampling Initial symptom: 2-4 years Head/face : Macrocephaly, delayed teeth eruption progressive hearing loss, thick lips, tongue and nostrils Heart : Thick heart valves Lung : obstructive airway disease Abdomen : Organomegaly Skeleton : Short neck, broad chest, joint stiffness, restricted joint movement 121

122. Management Poor prognosis Patient dies by the age of 15 years due to obstructive airway disease and cardiac complications Idursulfase, an enzyme replacement therapy (FDA, 2006) is the first treatment approved. 122

123. Syndromes primarily associated with Cleft Lip and Palate 123

124. Van der Woude Syndrome (Lip pits syndrome)  Anne Van der Woude: 1954 Incidence: 1 in 100000-200000 live births. Inheritance : AD   Mutations : Interferon regulatory factor 6 ( IRF6 ) 124

125. Diagnosis: clinical features, radiographs, molecular genetics 125

126. Pediatricians, Pedodontist , Plastic surgeons, Cosmetic surgeons, Maxillofacial surgeons, Speech pathologists, Otolaryngologists, Orthodontist Surgical correction of cleft lip/palate Surgical excision of lip pits Orthodontic correction of teeth Management: Multidisciplinary approach 126

127. Orofacial Digital Syndrome Mutation : CXORF5 Incidence: 1 in 50000 live birth. 127

128. OFDS Type I ( Papillon-Leage-Psaume Syndrome, XD) OFDS Type II (Mohr Syndrome, AR) OFDS Type III ( Sugarman Syndrome, AR) OFDS Type IV ( Baraitser -Burn Syndrome, AR) OFDS Type V (Thurston Syndrome, AR) 128

129. OFDS Type VI ( Varadi Syndrome, AR) OFDS Type VII (Whelan Syndrome, XD, AD) OFDS Type VIII (Edwards Syndrome, XR) OFDS Type IX (OFD Syndrome with Retinal Abnormalities, AR) OFDS Type X (OFD with Fibular Aplasia, AR) 129

130. Intellectual and central nervous system (CNS) development: Mental retardation, Seizures, Impeded development of speech and motor control Other: Growth retardation; heart malfunctioning; kidney malfunctioning; sunken chest; vulnerability to respiratory infection 130

131. Diagnosis: Clinical features, Maxillofacial imaging, Molecular genetics 131

132. Pediatricians, Pedodontist , Plastic surgeons, Cosmetic surgeons, Maxillofacial surgeons, Orthopedist, Speech pathologists, Otolaryngologists, Orthodontist, Pulmonologist, Opthalmologist , Neurologist, Nephrologist Surgical correction of cleft lip/palate Orthognathic surgery Orthodontic correction of teeth Surgical correction of tongue Management: Multidisciplinary approach 132

133. Miscellaneous syndromes 133

134. Ascher’s Syndrome Laffer-Ascher: 1920 Underlying cause is unknown Incidence: 10% Inheritance : Not inherited 134

135. Double lip Blepharochalasis Non toxic thyroid enlargement (goiter) Diagnosis 135

136. Management: Multidisciplinary Approach Opthalmologist , Endocrinologist, Dental specialist Esthetic/ Cosmetic surgery is the treatment of choice 136

137. Parry Romberg Syndrome (Hemifacial atrophy, Progressive facial hemiatrophy , Progressive hemifacial atrophy, Romberg syndrome) Parry: 1825, and Romberg: 1846 Progressive hemifacial atrophy: Eulenberg in 1871 Exact cause is unknown and appears to occur sporadically 137

138. Wartenburg : cerebral disturbance leads to increased, unregulated activity of SNS, produce localized atrophy through its tropic functions conducted by sensory trunks of trigeminal nerve. Incidence: 1 per 700000 live births. 138

139. Malformed pinna Progressive hearing loss Micropthalmia Alopecia Migraine Headache Epileptic seizures Hypo/Hyperpigmented areas in skin 139

140. Oral manifestations: Hemiatrophy lip Hemiatrophy tongue Hemiatrophy of muscles of mastication Hemiatrophy of mandible Hemi masticatory spasm Unusually small root of teeth Malocclusion Trigeminal neuralgia Diagnosis: clinical features, CT, MRI, Biopsy 140

141. Pediatricians, Surgeons (especially plastic surgeons), Dental specialist, Ophthalmologists, Dermatologists, Neurologists, Psychologist Cosmetic surgery of maxillofacial region Orthodontic correction of malocclusion Management of trigeminal Neuralgia (if present) Management: Multidisciplinary Approach 141

142. Beckwith- Widemann Syndrome (Beckwith-Syndrome, Exomphalos -Macroglossia-Gigantism Syndrome, Hypoglycemia with Macroglossia, Visceromegaly -Umbilical Hernia-Macroglossia Syndrome, Wiedemann-Beckwith Syndrome) Dr. John Bruce Beckwith and Dr. Hans-Rudolf Wiedemann: 1960s, independently reported cases and proposed new syndrome termed EMG ( exomphalos ,  macroglossia , and  gigantism) O ver time known as Beckwith–Wiedemann syndrome or Wiedemann Beckwith syndrome 142

143. Inheritance : AD Mutation : CDKN1C,   H19 ,  IGF2 , and  KCNQ1OT1 Incidence : 1 in 13700 live births. 143

144. Neonatal Hypoglycemia Hemihyperplasia /hemihypertrophy Organomegaly Nephrocalcinosis 144

145. Oral manifestations: Macroglossia Hemihypertrophy/ hemihyperplasia of face Malocclusion Mandibular prognathism Diagnosis: Clinical features, Blood glucose level, Molecular genetics Prenatal: Ultrasonography 145

146. Geneticists, Pediatricians, Plastic surgeons, Nephrologist, Dental specialists, Speech pathologists, Pediatric oncologists, Otorhinolaryngologist , Pulmonologist Feeding evaluation and sleep studies May undergo tongue reduction surgery (upper respiratory obstruction) Orthognathic surgery Orthodontic correction of malocclusion Management: Multidisciplinary Approach 146

147. Klinefelter Syndrome (Klinefelter- Reifenstein -Albright syndrome)  Harry Klinefelter: 1942, worked with Fuller Albright and E. C. Reifenstein Incidence: 1in 500-600 live births. Inheritance: not inherited Cause: an egg or sperm cell may gain one or more extra copies of the X chromosome as a result of nondisjunction, 47XXY 147

148. Diagnosis: Clinical features, Chromosome karyotype analysis on blood Prenatal: Amniocentesis, Chronic villous sampling 148

149. Management: Multidisciplinary approach Physicians, Endocrinologist, General surgeons, Dental specialist, psychologist, Geneticist Tricky extraction and Root Canal treatment of tooth with Taurodontism 149

150. Rubinstein– Taybi syndrome (Broad thumb-hallux syndrome, Rubinstein syndrome) Michail , Matsoukas and Theodorou : 1957, case Jack Herbert Rubinstein and Hooshang Taybi : 1963, case series Incidence: 1 per 125000 Inheritance : AD Mutation : CREBBP, EP300 150

151. Developmental delays Growth delays Speech delays Intellectual disability Craniofacial dysmorphism Recurrent respiratory infections Sleep apnea Ventricular septal defects Dysphagia Psychomotor delays Beak shaped nose Hypertelorism /ptosis Kyphosis Pectus excavatum Cryptorchidism 151

152. Oral manifestations: Small mouth Thin upper lip High arched palate Underdeveloped maxilla/ mandible Retrognathia Morphological alteration in tooth Crowding Talon’s cusp Bipid uvula Grimacing smile Diagnosis: clinical features, radiographs, molecular genetics, 152

153. Pediatricians, Cardiologists, Orthopedists, Audiologists, Urologist, Nephrologists, Dental specialists, Physiotherapist, Speech pathologists, Psychologist, Geneticist Othognathic surgery Orthodontic correction of malocclusion Removal of occlusal interferences if any Improvement in smile line Management: Multidisciplinary approach 153

154. Genetic services, Counselling and Screening 154

155. Organization of services: Regional genetic service center (clinical + laboratory skills) Family oriented Individual family records DNA “banked” from blood samples Genetic register Computerized follow up 155

156. Approach to Genetic Counselling: Prior to conception Establishing correct diagnosis: Challenge Number Rare Heterogeneity (Clinical/Molecular) Complications Prognosis Passing on to future generations OPTIONS: stress that reproductive decisions are purely personal than medical decision and counsellor’s approach remains non-directive 156

157. OPTIONS No further action Restrict Family size Adoption Artificial Insemination Ovum donation Flexible counsellor’s approach Sufficient time Open-ended questions Expression of feelings and emotions 157

158. Genetic screening in population Meet the following criteria: Useful outcome : Early diagnosis will improve treatment or allows reproductive choice. Socially and ethically acceptable Accurate with high sensitivity and specificity Cost effective 158

159. Way through… Karyotyping Gene mapping Polymerase chain reaction Ultrasonography 159

160. Genetic clinic in BPKIHS Pediatric OPD Every Wednesday from 2:00 pm onwards Genetic counselling History, Examination and Clinical diagnosis Multidisciplinary symptomatic management Genetic cases: Down syndrome Turner syndrome Metabolic disorders: Congenital hypothyroidism Congenital adrenal hyperplasia Inborn errors of metabolism: Fructose intolerance Galactosemia 160

161. Summary Syndromes of interest to dentist can be categorized by stage of development in which they become clinically identifiable. Syndromes identifiable soon after birth results from genetic defects or adverse influences during gestation. Syndromes that become apparent later in life is either genetically determined or acquired by various pathologic mechanisms. Many acquired syndromes consists of multiple clinical findings that are diverse pathophysiologic consequences of an underlying abnormality. 161

162. Syndrome with deficient mandible Syndrome with deficient maxilla Syndrome with connective tissue deficiency Syndrome with congenital skin anomaly Syndrome which become apparent after infancy Syndromes associated with fibro-osseous lesions of jaws Syndrome associated with red and white lesions of oral cavity Syndrome associated with facial nerve palsy Syndrome associated with mucopolysachharodosis Syndromes primarily associated with cleft lip/palate Miscellaneous syndromes 162

163. Conclusion Developmental syndromes with oral features present diagnostic challenge as most of them occur relatively rarely and limits clinicians ability to gain direct familiarity. Diverse manifestations characterize many syndromes which can occur coincidentally with several abnormality caused by unrelated conditions. Diagnosis requires correlation of pattern of observed abnormalities with features of recognized syndromes. Phasing out the negative societal influence and imparting positive attitude towards syndromic patient will help them live better and quality life. 163

164. Lets Recall… Micrognathia, glossoptosis and cleft palate is associated with Treacher Collins syndrome Mandibulofacial dysostosis Pierre Robins syndrome Crouzon syndrome 164

165. Which is not the feature of Apert Syndrome Wormian bones Hallux varus Acrocephaly Valgus deformity 165

166. The picture demonstrates________ in Ehlers Danlos syndrome Cigarette paper Scar Parchment scarring Limber Velvety skin 166

167. Gene associated with NBCCS is CTSC PTCH1 GNAS1 ACVRL1 167

168. Which of the following is mismatch Grinspan syndrome: HTN, DM, Lichen planus Mazabraud syndrome: GNAS1 Noonan syndrome: Noonan and Ehmke, 1963 Hereditary ectodermal dysplasia: Hypohydrosis , hypertrichosis, hypodontia 168

169. References: MCIntosh N, Helms P, Smyth R. Textbook of Pediatrics. 6 th Edition. Edinburgh: Churchill Livingstone, 2003 Glick M. Burket’s Oral Medicine. 12 th edition. Connecticut: PMPH, 2015 Wulfsburgh EA. Treacher Collins Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:262-3 Sakai D, Dixon J, Achilleos A, Dixon M, Trainor PA. Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation. Nat Commun . 2016; 21;7:10328 Yao CT, Wang JN, Tai YT, Tsai TY, Wu JM. Successful management of a neonate with Pierre-Robin syndrome and severe upper airway obstruction by long-term placement of a laryngeal mask airway. Resuscitation. 2004 Apr;61(1):97-9 Abu- Sittah GS, Jeelani O, Dunaway D, Hayward R. Raised intracranial pressure in Crouzon syndrome: incidence, causes, and management. J Neurosurg Pediatr . 2016;17:469-475 Long MD, Lin KYK. Crouzon Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:710-711 Passos -Bueno MR, Richier Costa A, Seritie AL, Kneppers A. Presence of the Apert canonical S252W FGFR2 mutation in a patient without severe syndactyly.  J Med Genet  1998;  35 : 677–679 Quintero-Rivera F, Robson CD, Reiss RE, Levine D, et al. Intracranial anomalies detected by imaging studies in 30 patients with Apert syndrome. Am J Med Genet A. 2006;140:1337-38 169

170. Roizen NJ, Patterson D. Down's syndrome. Lancet. 2003 Apr 12;361(9365):1281-9 Steingass KJ, Chicoine B, McGuire D, Roizen NJ. Developmental disabilities grown up: Down syndrome. J Dev Behav Pediatr . 2011 Sep;32(7):548-58 Mundlos S. Cleidocranial dysplasia: clinical and molecular genetics. J Med Genet 1999;36:177-182 Golan I, Baumert U, and Muessig D. Cleidocranial Dysplasia. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003: 182-3 Dietz H. Marfan Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:218-9 Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476-485 Dean JC. Marfan syndrome: clinical diagnosis and management. Eur J Hum Genet. 2007;15:274-33 McKusick VA. Ellis-van Creveld syndrome and the Amish. Nat Genet. 2000;24(3):283-6 Glavina D, et al. Hypohidrotic ectodermal dysplasia: dental features and carrier detection. Coll Antropol . 2001;25:303-10 Kargul B, et al. Hypohidrotic ectodermal dysplasia: dental, clinical, genetic and dermatoglyphic findings of three cases. J Clin Pediatr Dent. 2001;26:5-12 Comi AM. Sturge-Weber Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:258 170

171. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368:1971-1979 Burke, C. Peutz-Jeghers Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:351-2 McGarrity TJ, Kulin HE, and Zaino RJ. Peutz-Jeghers syndrome. Am J Gastroenterol. 2000;95:596-604 Randall W Burt, MD. Gardner syndrome.  UpToDate . January 2015 Gorlin RJ. Nevoid basal cell carcinoma ( Gorlin ) Syndrome. Genet Med. 2004;6:530-539 Gorlin RJ. Nevoid basal cell carcinoma ( Gorlin ) syndrome. In: Neurocutaneous Syndromes, Roach ES, Miller VS, editors. 2004 Cambridge University Press, New York, NY. Pp. 77-87 Samad A, Mohan N, Balaji RV, et al; Oral manifestations of plummer-vinson syndrome: a classic report with literature review. J Int Oral Health. 2015 Mar 7(3):68-71 Novacek G; Plummer-Vinson syndrome. Orphanet J Rare Dis. 2006 Sep 15 1:36 Lee JS, FitzGibbon EJ, Chen YR, et al. Clinical guidelines for the management of craniofacial fibrous dysplasia. Orphanet J Rare Dis. 2012;7( Suppl 1):S2 Salenave S, Boyce AM, Collins MT, Chanson P. Acromegaly and McCune-Albright syndrome. J Clin Endocrinol Metab . 2014;99:1955-19969 Chapurlat RD, Gensburger D, Jimenez-Andrade JM, et al. Pathophysiology and medical treatment of pain in fibrous dysplasia of bone. Orphanet J Rare Dis. 2012;7:S3 171

172. Allanson JE. Noonan Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins; 2003: 722-723 Faughnan , M. E., et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. Journal of medical genetics. 2011:48.2:73-87 McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management and pathogenesis. Genet Med 2011;13:607 Lamey PJ, Gibson J, Barclay SC, Miller S. Grinspans’s syndrome: A drug-induced phenomenon? Oral Surg Oral Med oral Pathol 1990;70:184-5 Borghelli R.F., Pettinari I.L., Chuchurru J.A., et.al. Oral lichen planus in patients with diabetes. An epidemiologic study. Oral Surg. Oral Med. Oral Pathol ; 1993: 75, pp. 498-500 Ramesh BA. Ascher syndrome: Review of literature and case report.  Indian J Plast Surg . 2011 Jan-Apr; 44(1):147-149 Dutt SN and Irving RM. Melkersson -Rosenthal Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:557 Kovich OI and Cohen DE. Granulomatous cheilitis. Dermatology Online Journal 2004;10(3):10 Susser WS, Chapman MS. Parry-Romberg Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:232-233 El- Kehdy J, Abbas O, Rubeiz N. A review of Parry-Romberg syndrome. J Am Acad Dermatol 2012;67:769–84 172

173. Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann Syndrome. Am J Med Genet C Semin Med Genet. 2010; 154C:343–54 Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2169-76 Muenzer J and Fisher A. Advances in the Treatment of Mucopolysaccharidosis Type I. New Engl J Med. 2004;350:1932-34 Wraith JE, Scarpa M, Beck M, et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. European Journal of Pediatrics. 2008;167(3):267-277. doi:10.1007/s00431-007-0635-4 Wattendorf DJ, Muenke M. Klinefelter syndrome. Am Fam Physician. 2005;72(11):2259-62 Rubinstein JH. Rubinstein- Taybi Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:726-7 Houweling AC, Gille JJP, Baart JA, van Hagen JM, Lachmeijer AM. Variable phenotypic manifestation of IRF6 mutations in the Van der Woude syndrome and popliteal pterygium syndrome: implications for genetic counseling. Clin Dysmorphol . 2009;18:225-227 Driva T, Franklin D, Crawford PJ. Variation in expression of oral-facial-digital syndrome (type I): report of two cases. Int J Paediatr Dent. 2004;14:61-68 Neville BW, Doughlas D, Allen C, Bouquot J. Oral and Maxillofacial Pathology. 3 rd edition. Philadelphia: Saunders Elsevier, 2014 Rajendran R, Sivapathasundharam B. Shafer’s Textbook of Oral Pathology. 6 th edition. India: Elsevier, 2009 Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry. 2001;71:149-54 Coleman G, Nelson J. Principles of Oral Diagnosis. Mosby, 1993 Gorlin R, Cohen M, Hennekam R. Syndromes of the head and neck. 4 th edition. New York: Oxford, 2001 173

174. Thank you !!! 174

175. Discussion: Down syndrome and caries:  Salivary S. mutans (serotype g and c) specific IgA concentrations were significantly higher in Down syndrome children leading to lower incidence of dental caries. Lee SR et al,. Dental caries and salivary immunoglobulin A in Down syndrome children. J Paediatr Child Health. 2004 Sep-Oct;40(9-10):530-3 175

176. Low set ears: The ear is low-set when the helix of the ear meets the cranium at a level below that of a horizontal plane through both inner canthi (the inside corners of the eyes) Sivan Y, Merlob P, Reisner SH (June 1983). "Assessment of ear length and low set ears in newborn infants".  J. Med. Genet .  20  (3): 213–5 176

177. Oral surgical considerations (Extraction) in Ehlers Danlos Syndrome Avoided as far as possible. Clotting profiles should be checked prior to extraction. Desmopressin may be indicated. Mucoperiosteal flap should be raised with care. Absorbable haemostatic agents to be applied after extraction. Better to tie sutures under slight tension, taking larger sections of tissue. Care must be taken while using forceps and applying pressure to gums and surrounding structures. Pre-fabricated acrylic plate may be required over extraction site. Dentistry Medical Resource Guide, 2007. Ehlers Danlos National foundation. 177

178. Pinky in Apert syndrome Pinky: involves syndactyly of Pinky finger (little finger)   Flatt A (1 January 2005). "Webbed fingers". Proceedings (Baylor University. Medical Center).  18  (1): 26–37 178

179. Infective endocarditis prophylaxis: Robin sequence Apert syndrome Ehlers Danlos syndrome Marfan syndrome Ellis Van Creveld syndrome 179

180. Surgical options for airway obstructions in Robin sequence Tracheostomy (Gold Standard) Nasopharyngeal airway Tongue-lip adhesion Distraction osteogenesis of mandible. Marcellus L. The infant with Pierre Robin sequence: review and implications for nursing practice. J Pediatr Nurs . 2001;16(1):23–34 180

181. Height (short stature) Nepal Male: 163 cm (5 feet 4 inch) Female: 150 cm (4 feet 11 inch) Subramanian, S. V.; Özaltin , Emre; Finlay, Jocelyn E. (2011). "Height of Nations: A Socioeconomic Analysis of Cohort Differences and Patterns among Women in 54 Low- to Middle-Income Countries 181

182. 182

183. 183

184. 184 Bifurcation is slightly apical to normal. Bifurcation at the middle of the root. Bifurcation at apical one third or no bifurcation at all.

185. In which week of 2nd trimester morphologic alteration in Usg is seen 18-23 weeks. Diagnosis of fetal abnormalities-The 18-23 weeks scan. Fetal medicine Foundation, London 185

186. Different forms of iron and iron supplement Ferrous fumarate Ferrous gluconate Ferrous sulfate Does: 120 mg iron + 400 µg folic acid daily for 3 months DeMaeyer EM, Dallman P, Gurney JM, et al (1989) Preventing and controlling iron deficiency anaemia through primary health care: a guide for health administrators and programme managers. Geneva: World Health Organization Gillespie S, Kevany J, Mason J (1991) Controlling iron deficiency. ACC/SCN Stateof -the-Art Series Nutrition Policy Discussion Paper No. 9. United Nations 186

187. Genetic clinic around the country Bir Hospital IOM 187

188. Chediak Higashi Syndrome ( Begnez -Cesar's Syndrome, Chediak - Steinbrinck -Higashi Syndrome, CHS, Leukocytic Anomaly Albinism, Natural Killer Lymphocytes, Defect in, Oculocutaneous Albinism, Chediak -Higashi Type) Chediak and Higashi: 1952 and 1954 Mutation: CHS 1 gene encoding lysosomal trafficking protein. Inheritance: AR Incidence: less than 500 cases has been reported in last 20 years. 188

189. Partial oculocutaneous albinism. Easy bruisability and bleeding(result of deficient platelet dense bodies). Abnormal natural killer cell function Ulcerations of the Oral Mucosa Severe Gingivitis and Glossitis Periodontitis (probably related to defective leukocyte function) 189

190. Management No specific treatment. Often fatal. Death occurring before child reaches the age of 10 years 190

191. Difference between lichen planus and lichenoid reaction Neither clinical nor histopathologic features enable discrimination between different lichenoid reactions: Oral lichen planus Lichenoid contact reactions Lichenoid drug eruptions Lichenoid reactions of graft-versus-host disease (GVHD) 191

192. Antihypertensive and oral hypoglycemic causing lichenoid reaction Antihypertensive: ACE inhibitors (Captopril, Lisonopril ) Oral hypoglycemic: Metformin 192

193. Telangiectasia Telangiectasia  is a condition in which widened venules (tiny blood vessels) cause threadlike red lines or patterns on the skin. These patterns, or telangiectases , form gradually and often in clusters. They're sometimes known as “spider veins” because of their fine and weblike appearance. 193

194. Diagnosis of Polycythemia vera : WHO 2016 Major criteria: Hemoglobin >16.5 g/ dL in men and >16 g/ dL in women, or hematocrit >49% in men and >48% in women, or red cell mass >25% above mean normal predicted value Bone marrow biopsy showing hypercellularity for age, including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size) Presence of  JAK2 V617F or  JAK2  exon 12 mutation Minor criteria: Serum erythropoetin level below normal. 194

195. Criterion 2 (bone marrow biopsy) may not be required in patients who have sustained absolute erythrocytosis (in men, hemoglobin/hematocrit of >18.5 g/ dL /55.5% or in women, >16.5 g/ dL /49.5%) if major criterion 3 and the minor criterion are present. All 3 major criteria or first 2 major criteria and minor criteria. 195

196. Investigations for HHT Ideally no laboratory studies are widely available to confirm the diagnosis of HHT. Oximetry is performed with the patient standing and supine for 10 minutes in each position. An oxygen saturation level of less than 96% in either position is considered an indication for further testing. When a complete blood count (CBC) is done, hemoglobin may be decreased because of chronic bleeding and iron-deficiency anemia, or the patient may be polycythemic because of chronic hypoxemia from a right-to-left shunt The platelet count may be normal or slightly increased. . 196

197. The white blood cell (WBC) count should be within the reference range unless an infectious complication ( eg , a brain abscess) is present. Coagulation profile findings may exclude a concurrent disorder or coagulopathy. Prothrombin time (PT) and activated partial thromboplastin time ( aPTT ) values should be normal, unless severe liver involvement is present. Urinalysis should be done to assess for hematuria.     Stool should be evaluated to look for the presence of blood. Liver function tests may be deranged. 197

198. Arterial blood gas measurement can also be used as a screening test for pulmonary AVM. The quantification of a right-to-left shunt can be measured with the patient breathing 100% oxygen for at least 20 minutes. Giordano P, Lenato GM, Suppressa P, Lastella P, Dicuonzo F, Chiumarulo L, et al. Hereditary hemorrhagic telangiectasia: arteriovenous malformations in children.  J Pediatr . 2013 Jul. 163(1):179-86.e1-3 Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia.  N Engl J Med . 1995 Oct 5. 333(14):918-24 198

199. Iron supplement: to prevent iron deficiency anemia; PV syndrome Iron rich foods: Red meat, pork and poultry Seafood Beans Dark green leafy vegetables, such as spinach Dried fruit, such as raisins and apricots Iron-fortified cereals, breads and pastas Peas 199 Vitamin C to enhance iron absorption Broccoli Grapefruit Kiwi Melons Oranges Strawberries Tomatoes Baker, S. J., and E. M. DeMaeyer . 1979. Nutritional anemia: its understanding and control with special reference to the work of the World Health Organization.  Am. J. Clin . Nutr .  32:368–417. Ballot, D. E., A. P. McPhail, T. H. Bothwell, M. Gillooly , and F. G. Mayet . 1989a. Fortification of curry powder with NaFe (III)EDTA in an iron deficient population: initial survey of iron status.  Am. J. Clin . Nutr .  49:156–161

200. Differential diagnosis of claw hands: Hurler’s syndrome Hunter’s syndrome Leprosy Gout, Pseudogout Muscular dystrophy Charcoat Marry tooth disease Lyme disease Whipple’s disease Reactive arthritis Systemic lupus erythematosus Sarcododsis 200 Sapienza, A., & Green, S. (2012). Correction of the claw hand. Hand Clin, 28(1), 53-66. doi: 10.1016/j.hcl.2011.09.009

201. Differential diagnosis of multiple impacted teeth Cleidocranial dysplasia Down syndrome Gardner’s syndrome Noonan syndrome Osteopetrosis Mucopolysachharadosis Apert syndrome Crouzon syndrome Ehlers Danlos dyndrome Klippel- Trenaunay syndrome Orofacial digital syndrome Sturge Weber syndrome 201 Bayar G, Ortakoglu K, sensimen M. Multiple impacted tooth: report of three cases and review of literature. Eur J Dent. 2008 Jan; 2: 73–78

202. Vanishing Maxilla Gorham Stout syndrome Spontaneous and progressive resorption and disappearance of osseous structures which is replaced by vascular connective tissue.  Although the disease is progressive and can be severely disfiguring, it is rarely fatal. It may progress unremittingly over years but can also spontaneously arrest The osteoclast precursors of the patient with osteolysis were found to be more sensitive to stimulating and humoral factors, such as receptor activator of nuclear factor kappa B ligand (RANKL) and interleukin-6, and produce greater lacunar resorption 202

203. 203 Gorham LW, Wright AW, Shultz HH, Maxon FC., Jr Disappearing bones: a rare form of massive osteolysis; report of two cases, one with autopsy findings. Am J Med 1954;17:674–682  Lee S, Finn L, Sze RW, Perkins JA, Sie KC. Gorham Stout syndrome (disappearing bone disease): two additional case reports and a review of the literature. Arch Otolaryngol Head Neck Surg  2003;129:1340–1343

204. Lobulated tongue in OFDS These are called as lingual Hamartomas. Mutation in DDX59 gene Oral-facial digital syndrome. Genetics home reference. ghr.nlm.nih.gov/condition/oral-facial digital syndrome. Reviewed: February 2010, Published: January 17, 2013 204

205. Cathepsin C: function Cathepsin C  ( CTSC ) also known as  dipeptidyl peptidase I  ( DPP-I ) is a lysosomal  exo -cysteine protease belonging to the peptidase C1 family. Cathepsin C catalyses excision of dipeptides from the N-terminus of protein and peptide substrates. Cathepsin C functions as a key enzyme in the activation of granule serine peptidases in inflammatory cells, such as elastase and cathepsin G in neutrophils cells and chymase and tryptase in mast cells. Hola-Jamriska L, Tort JF, Dalton JP, Day SR, Fan J, Aaskov J, Brindley PJ (Aug 1998). "Cathepsin C from Schistosoma japonicum--cDNA encoding the preproenzyme and its phylogenetic relationships".  European Journal of Biochemistry / FEBS .  255  (3): 527–34 205

206. Average inner intercanthal distance: 20-35 mm Average interpupillary distance: 45-70 mm Outer intercanthal distance: 75-105mm Resident Manual of Trauma to the Face, Head, and Neck, Ed. 1"" (PDF). Retrieved 12 January 2015 206