26
Agnathia is an extremely rare lethal neurocristopathy. The disorder has also been termed agnathia-holoprosencephaly, agnathia-astomia-synotia, or cyclopia-otocephaly association.
The incidence is estimated to be 1/132,000 births in Spain.
GENETICS/BASIC DEFECTS
1. Sporadic occurrence in majority of cases 2. Rare autosomal recessive inheritance 3. Possible autosomal dominant inheritance
a. Supported by an observation of dysgnathia in mother and daughter
b. Possibility of a defect in the OTX2 gene as the basis of the disorder
4. A prechordal mesoderm inductive defect affecting neural crest cells
a. A developmental field defect
b. Different etiologic agents (etiological heterogeneity) acting on the same developmental field producing a highly similar complex of malformations
5. Possible existence of a mild form of agnathia without brain malformation (holoprosencephaly)
a. Situs inversus-congenital hypoglossia
b. Severe micrognathia, aglossia, and choanal atresia 6. A well-recognized malformation complex in the mouse,
guinea pig, rabbit, sheep, and pig
CLINICAL FEATURES
1. Polyhydramnios due to persistence of oropharyngeal membrane or blind-ending mouth
2. Agnathia (absence of the mandible)
3. Microstomia or astomia (absence of the mouth) 4. Aglossia (absence of the tongue)
5. Blind mouth 6. Ear anomalies
a. Otocephaly (variable ear positions)
b. Synotia (external ears approaching one another in the midline)
c. Dysplastic inner ear d. Atretic ear canal
7. Down-slanting palpebral fissures 8. Variable degree of holoprosencephaly
a. Cyclopia b. Synophthalmia c. Arrhinencephaly 9. Other brain malformations
a. Cerebellar hypoplasia b. Septum pellucidum Cavum c. Absence of cranial nerves (I-IV) d. Absence of the corpus callosum e. Meningocele
10. Intrauterine growth retardation
11. Cleft lip/palate 12. Occular malformations
a. Microphthalmos/anophthalmia b. Proptosis (protruding eyes) c. Absence of the eyelids d. Epibulbar dermoid e. Aphakia
f. Retinal dysplasia g. Microcornea
h. Anterior segment dysgenesis i. Uveal colobomas
13. Nasal anomalies
a. Absence of the nasal cavity b. Cleft nose
c. Blind nasal pharynx 14. Various visceral malformations
a. Choanal atresia
b. Tracheoesophageal fistula c. Absence of the thyroid gland
d. Absence of the submandibular and parotid salivary glands
e. Abnormal glottis and epiglottis f. Thyroglossal duct cyst
g. Carotid artery anomalies h. Situs inversus
i. Cardiac anomalies j. Unlobulated lungs k. Renogenital anomalies
i. Unilateral renal agenesis ii. Renal Ectopia
iii. Cystic kidneys iv. Horseshoe kidneys
v. Solitary kidney
vi. Mullerian duct agenesis vii. Cryptorchidism 15. Skeletal anomalies
a. Vertebral anomalies b. Rib anomalies c. Tetramelia 16. Anatomical variations
a. Ears
i. Absence of the tragus ii. Synotia
b. Mandible i. Rudimentary ii. Absent
iii. Two small separate masses
c. Mouth: microstomia with vertical orientation d. Buccopharyngeal membrane: absent to present e. Tongue
i. Small to absent body ii. Present in (hypo)pharynx f. Absent submandibular glands
Agnathia
AGNATHIA 27
g. Other skull bones: approximated maxillae, palatine, zygomatic, and temporal
DIAGNOSTIC INVESTIGATIONS
1. Radiography a. Reduced maxilla
b. Absence of the zygomatic process c. Absence of the hyoid bone d. Vertebral anomalies e. Absence of the ribs
f. Sprengel deformity
2. Cranial ultrasonography to define holoprosencephaly 3. Chromosome analysis
a. Normal in majority of cases
b. Unbalanced der(18),t(6;18)(pter →p24.1;p11.21→qter) in two female sibs with agnathia-holoprosencephaly 4. Autopsy to define postmortem findings
GENETIC COUNSELING
1. Recurrence risks
a. Risk to patient’s sib: not increased unless in a rare autosomal recessive inheritance
b. Risk to patient’s offspring: not applicable since affected patients do not survive to reproduce
2. Prenatal diagnosis by ultrasonography or three-dimensional imaging by helical computed tomography (CT)
a. Polyhydramnios
b. Intrauterine growth retardation
c. Mandibular absence (agnathia) or major hypoplasia d. Holoprosencephaly
e. Cyclopia, marked hypotelorism or frontal proboscis 3. Management: a lethal entity
REFERENCES
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Blaas HG, Eriksson AG, Salvesen KA, et al.: Brains and faces in holoprosen- cephaly: pre- and postnatal description of 30 cases. Ultrasound Obstet Gynecol 19:24–38, 2002.
Carles D, Serville F, Mainguene M, et al.: Cyclopia-otocephaly association: a new case of the most severe variant of Agnathia-holoprosencephaly com- plex. J Craniofac Genet Dev Biol 7:107–113, 1987.
Cohen MM: Perspectives on holoprosencephaly: Par III. Spectra, distinctions, continuities and discontinuities. Am J Med Genet 34:271–288, 1989.
Ebina Y, Yamada H, Kato EH, et al.: Prenatal diagnosis of agnathia-holopros- encephaly: three-dimensional imaging by helical computed tomography.
Prenat Diagn 21:68–71, 2001.
Erlich MS, Cunningham ML, Hudgins L: Transmission of the dysgnathia com- plex from mother to daughter. Am J Med Genet 95: 269–274, 2000.
Gaba AR, et al.: Alobar holoprosencephaly and otocephaly in a female infant with a normal karyotype and placental villitis. J Med Genet 19:78, 1982.
Henekam RC: Agnathia-holoprosencephaly: a midline malformation associa- tion. Am J Med Genet 36:525, 1990.
Hersh JH, McChane RH, Rosenberg EM, et al.: Otocephaly-midline malforma- tion association. Am J Med Genet 34:246–249, 1989.
Hinojosa R, Green JD, Brecht K, et al.: Otocephalus: histopathology and three- dimensional reconstruction. Otloaryngol Head neck Surg 114:44–53, 1996.
Johnson WW, Cook JB: Agnathia associated with pharyngeal isthmus atresia and hydramnios. Arch Pediatr 78:211–217, 1961.
Kamiji T, Takagi T, Akizuki T, et al.: A long surviving case of holoprosen- cephaly agnathia series. Br J Plast Surg 44:386–389, 1991.
Krassikoff N, Sekhon GS: Familial agnathia-holoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheri- tance. Am J Med Genet 34:255–257, 1989.
Lawrence D, Bersu ET: An anatomical study of human otocephaly. Teratology 30:155–165, 1985.
Leech RW, Bowlby LS, Brumback RA, et al.: Agnathia, holoprosencephaly, and situs inversus: report of a case. Am J Med Genet 29:483–490, 1988.
Meinecke P, Padberg B, Laas R: Agnathia, holoprosencephaly, and situs inver- sus: a third report. Am J Med Genet 37:286–287, 1990.
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Pauli RM, Pettersen JC, Arya S, et al.: Familial agnathia-holoprosencephaly.
Am J Med Genet 14:677–698, 1983.
Rolland M, Sarramon MF, Bloom MC: Astomia-agnathia-holoprosencephaly association. Prenatal diagnosis of a new case. Prenat Diagn 11:199–203, 1991.
Santana SM et al.: Agnathia and associated malformations. Dysmorph Clin Genet 1:58–63, 1987.
Scholl HW Jr: In utero diagnosis of agnathia, microstomia, and synotia. Obstet Gynecol 49(1 Suppl):81–83, 1977.
Suda Y, Nakabayashi J, Matsuo I, Aizawa S: Functional equivalency between Otx2 and Otx1 in development of the rostral head. Development 126:
743–757, 1999.
28 AGNATHIA
Fig. 1. A neonate (28 week gestation) with agnathia-holoprosen- cephaly complex showing a large defect involving entire midface area with almost total absence of jaw, absence of eyes and nose, and severe microtia. Absence of olfactory bulbs and grooves (arrhinencephaly) were demonstrated by necropsy. Additional anomalies included 13 pairs of ribs, atresia of left ureter with resultant hydronephrosis, and left renal cortical cysts. Maternal hydramnios was present.
