Oculo-Auriculo-Vertebral Spectrum (First and Second Branchial Arch Syndrome, Facio-Auriculo-Vertebral Spectrum, Hemifacial Microsomia, Goldenhar Syndrome)
The predominant defects in this spectrum represent problems in morphogenesis of the first and second branchial arches, sometimes accompanied by vertebral anomalies, renal defects, or ocular anomalies. The occurrence of epibulbar dermoid with this pattern of anomaly, especially when accompanied by vertebral anomalies, was designated as the Goldenhar syndrome, and the predominantly unilateral occurrence was designated as hemifacial microsomia. However, the occurrence of various combinations and gradations of this pattern of anomalies, both unilateral and bilateral, with or without epibulbar dermoid, and with or without vertebral anomalies, has suggested that hemifacial microsomia and the Goldenhar syndrome may simply represent variable manifestations of a similar error in morphogenesis. The frequency of occurrence is estimated to be 1 in 3000 to 1 in 5000, and there is a slight (3:2) male predominance.
Abnormalities
Variable combinations of the following, tending to be asymmetric and 70% unilateral.
Face. Hypoplasia of malar, maxillary, or mandibular region, especially ramus and condyle of mandible and temporomandibular joint; lateral cleft-like extension of the corner of the mouth (macrostomia); hypoplasia of facial musculature; hypoplasia of depressor anguli oris.
Ear. Microtia, accessory preauricular tags or pits, most commonly in a line from the tragus to the corner of the mouth; middle ear anomaly with variable deafness.
Oral. Diminished to absent parotid secretion, anomalies in function or structure of tongue, malfunction of soft palate.
Vertebral. Hemivertebrae or hypoplasia of vertebrae, most commonly cervical, but may also be thoracic or lumbar.
Central Nervous System. Hydrocephalus, Arnold-Chiari malformation, occipital encephalocele, agenesis of corpus callosum, calcification of falx cerebri, hypoplasia of septum pellucidum, enlarged ventricles, intracranial dermoid cyst, lipoma in corpus callosum, polymicrogyria.
Occasional Abnormalities
Eye. Epibulbar dermoid, lipodermoid, notch in upper lid, strabismus, microphthalmia.
Ear. Inner ear defect.
Oral. Cleft lip, cleft palate.
Cardiac. Ventricular and atrial septal defects, patent ductus arteriosus, tetralogy of Fallot, conotruncal defects, and coarctation of aorta, in decreasing order of frequency.
Genitourinary. Ectopic or fused kidneys, renal agenesis, vesicoureteral reflux, ureteropelvic junction obstruction, ureteral duplication, and multicystic dysplastic kidney.
Other. Intellectual disability (IQ below 85 in 13%), speech delay, autism, abnormal caruncles, branchial cleft remnants in anterior-lateral neck, laryngeal anomaly, hypoplasia to aplasia of lung, esophageal atresia, tracheomalacia caused by extrinsic vascular compression, radial and/or rib anomalies, prenatal growth deficiency, low scalp hairline.
Natural History
Reconstructive surgery is strongly indicated. Most of these patients are of normal intelligence. Intellectual disability is more common in association with microphthalmia. Deafness should be tested for at an early age.
Etiology
The cause of this disorder is unknown; cases are usually sporadic. Estimated recurrence in first-degree relatives is approximately 2%, although minor features of this disorder may be more commonly noted in relatives. When unilateral, it tends to be right-sided. Maternal diabetes has been associated in some cases. Del 22q11.2 has been reported in three cases. Based on studies utilizing an animal model, Poswillo concluded that this disorder was caused by interference with vascular supply and focal hemorrhage in the developing first and second branchial arch.
Comment
This spectrum occurs more frequently in one member of a monozygotic twin pair and has been seen in increased frequency following assisted reproductive techniques.
References
Goldenhar M: Associations malformatives de l’oeil et de l’oreille, J Genet Hum 1:243, 1952.
Summitt RL: Familial Goldenhar syndrome, Birth Defects 5:106, 1969.
Pashayan H, et al: Hemifacial microsomia-oculo-auriculo-vertebral dysplasia: A patient with overlapping features, J Med Genet 7:185, 1970.
Baum JL, Feingold M: Ocular aspects of Goldenhar’s syndrome, Am J Ophthalmol 75:250, 1973.
Poswillo D: The pathogenesis of the first and second branchial arch syndrome, Oral Surg 35:302, 1973.
Rollnick BR, et al: Oculoauriculovertebral dysplasia and variants: Phenotypic characteristics of 294 patients, Am J Med Genet 26:631, 1987.
Cohen MM Jr, et al: Oculoauriculovertebral spectrum: An updated critique, Cleft Palate J 26:276, 1989.
Ritchey ML, et al: Urologic manifestations of Goldenhar syndrome, Urology 43:88, 1994.
Nijhawan N, et al: Caruncle abnormalities in the oculo-auriculo-vertebral spectrum, Am J Med Genet 113:320, 2002.
Wang R, et al: Infants of diabetic mothers are at increased risk for the oculo-auriculo-vertebral sequence: A case-based and case-control approach, J Pediatr 141:611, 2002.
Strömland K, et al: Oculo-auriculo-vertebral spectrum: Associated anomalies, functional deficits and possible developmental risk factors, Am J Med Genet 143:1317, 2007.
Wieczorek D, et al: Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculo-auriculo-vertebral spectrum/Goldenhar syndrome, Hum Genet 121:369, 2007.
Digilio MC, et al: Congenital heart defects in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome), Am J Med Genet 146:1815, 2008.
Digilio MC, et al: Three patients with oculo-auriculo-vertebral spectrum and microdeletion 22q11.2, Am J Med Genet A 149A:2860, 2009.
FIGURE 1
Oculo-auriculo-vertebral spectrum.
A and B, Note the marked facial asymmetry and malformed ear. C, Note the epibulbar lipodermoids. D, Note the microtia and micrognathia.
Courtesy Dr. Lynne M. Bird, Rady Children’s Hospital, San Diego, California; D, Courtesy Dr. Michael Cohen, Dalhousie University, Halifax, Nova Scotia.
FIGURE 2
Note the variable features including the lateral cleft-like extension of the mouth (A), preauricular tags (B), and microtia (C). D, Encephalocele. E, Vertebral anomalies.
Courtesy Dr. Lynne Bird, Rady Children’s Hospital, San Diego, California; D , Courtesy Dr. Michael Cohen, Dalhousie University, Halifax, Nova Scotia.
Oromandibular-Limb Hypogenesis Spectrum (Hypoglossia-Hypodactyly Syndrome, Aglossia-Adactyly Syndrome, Glossopalatine Ankylosis Syndrome, Facial-Limb Disruptive Spectrum)
Limb Deficiency, Hypoglossia, Micrognathia
In 1932, Rosenthal described aglossia and associated malformations. Kaplan and colleagues emphasized a “community” or spectrum of disorders and suggested common elements in modes of developmental pathogenesis.
Abnormalities
Various combinations from among the following features.
Craniofacial. Small mouth, micrognathia, hypoglossia, variable clefting or aberrant attachments of tongue; mandibular hypodontia; complete bony fusion of the maxilla and mandible, choanal atresia, cleft palate; cranial nerve palsies, including Moebius sequence; broad nose; telecanthus; lower eyelid defect; facial asymmetry.
Limbs. Hypoplasia of varying degrees, to point of adactyly; syndactyly, angel-shaped phalanx.
Other. Brain defects, especially of cranial nerve nuclei, causing Moebius sequence; splenogonadal fusion, hypoplasia of atlas with craniocervical junction malformation, gastroschisis.
Natural History
Early feeding and speech difficulties may occur. Orthopedic and/or plastic surgery may be indicated for the limb problems. Intelligence and stature are generally normal. Serious problems with hyperthermia can occur in children with four-limb amputation.
Etiology
The cause of this disorder is unknown; cases are usually sporadic. The hypothesis that the abnormalities are the disruptive consequence of hemorrhagic lesions has experimental backing from the studies of Poswillo. The presumed vascular problem is more likely to occur in distal regions, such as the distal limbs, tongue, and occasionally parts of the brain. Chorionic villus sampling, particularly when performed between 56 and 66 days of gestation, has been associated with this disorder, as has the use of misoprostol as an abortifacient, giving further credence to a disruptive vascular pathogenesis.
References
Rosenthal R: Aglossia congenita: A report of the condition combined with other congenital malformations, Am J Dis Child 44:383, 1932.
Poswillo D: The pathogenesis of the first and second branchial arch syndrome, Oral Surg 35:302, 1973.
Kaplan P, et al: A “community” of face-limb malformation syndromes, J Pediatr 89:241, 1976.
Pauli RM, Greenlaw A: Limb deficiency and splenogonadal fusion, Am J Med Genet 13:81, 1982.
Lipson AH, Webster WS: Transverse limb deficiency, oro-mandibular limb hypogenesis sequences, and chorionic villus biopsy: Human and animal experimental evidence for a uterine vascular pathogenesis, Am J Med Genet 47:1141, 1993.
Knoll B, et al: Complete congenital bony syngnathia in a case of oromandibular limb hypogenesis, J Craniofac Surg 11:398, 2000.
Kiliç N, et al: Oromandibular limb hypogenesis and gastroschisis, J Pediatr Surg 36:E15, 2001.
Camera G, et al: “Angel-shaped phalanx” in a boy with oromandibular-limb hypogenesis, Am J Med Genet 119:87, 2003.
Al Kaissi AA, et al: Cervicocervical junction malformation in a child with oromandibular-limb hypogenesis-Möbius syndrome, Orphanet Journal of Rare Diseases 2:2, 2007.
FIGURE 1
Oromandibular-limb hypogenesis spectrum.
No one instance is the same as the next. There are varying degrees of limb deficiency, hypoglossia, or micrognathia. A–C, Necropsy photograph of a newborn. D, Note that the child has Moebius sequence as an associated feature. E–G, This child has splenogonadal fusion as an associated feature.
Congenital Microgastria–Limb Reduction Complex (Microgastria, Limb Defects, Splenic Abnormalities)
Robert described the first patient with this disorder in 1842. Subsequently, 16 additional cases have been described.
Abnormalities
Gastrointestinal. Microgastria, intestinal malrotation.
Limb. Varying degrees of radial and ulnar hypoplasia, bilateral in 40% of cases; isolated absence of thumbs (20%); terminal transverse defects of humerus (10%); phocomelia (10%); oligodactyly.
Spleen. Abnormalities in 70%, including asplenia, hyposplenia, or splenogonadal fusion.
Other. Renal anomalies in 50%, including pelvic kidney in two cases and unilateral renal agenesis and bilateral cystic dysplasia in one patient each; defects in laterality; cardiac defects in 20% (secundum atrial septal defect and type I truncus arteriosus); central nervous system defects in 20% (arrhinencephaly, fused thalami, polymicrogyria, agenesis of corpus callosum, and hydrocephalus).
Occasional Abnormalities
Congenital megacolon, esophageal atresia, anal atresia, abnormal lung lobation, anophthalmia and porencephalic cyst, amelia, cryptorchidism, bicornuate uterus, horseshoe kidney, and absent gallbladder.
Natural History
Microgastria usually presents with gastroesophageal reflux and failure to thrive. Death before 6 months of age has occurred in almost 50% of cases. Surgical intervention to create a gastric reservoir improves the ability of patients to tolerate normal feeding volumes.
Etiology
The cause of this disorder is unknown. All cases have represented sporadic events in otherwise normal families. The occurrence of three cases in which discordance for this disorder has occurred in twins is noteworthy.
References
Robert HLF: Hummungsbildung des Magens, Mangel der Milz und des Netzes, Arch Anat Physiol Wissenschaftliche Med 57, 1842.
Lueder GT, et al: Congenital microgastria and hypoplastic upper limb anomalies, Am J Med Genet 32:368, 1989.
Meinecke P, et al: Microgastria–hypoplastic upper limb association: A severe expression including microphthalmia, single nostril and arrhinencephaly, Clin Dysmorphol 1:43, 1992.
Cunniff C, et al: Congenital microgastria and limb reduction defects, Pediatrics 91:1192, 1993.
Lurie IW, et al: Microgastria–limb reduction complex with congenital heart disease and twinning, Clin Dysmorphol 4:150, 1995.
