ß 2007 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 143A:1317 – 1325 (2007)
Oculo-Auriculo-Vertebral Spectrum: Associated Anomalies, Functional Deficits and Possible Developmental Risk Factors ¨ mland,1* Marilyn Miller,2 Lotta Sjo ¨ green,3 Maria Johansson,4 Kerstin Stro 5 4 Britt-Marie Ekman Joelsson, Eva Billstedt, Christopher Gillberg,4 Susanna Danielsson,6 ¨ sta Granstro ¨ m7 Catharina Jacobsson,3 Jan Andersson-Norinder,3 and Go 1 Department of Ophthalmology, The Sahlgrenska Academy at Go¨teborg University, Go¨teborg, Sweden Department of Ophthalmology & Visual Sciences, Eye and Ear Infirmary, University of Illinois, Chicago, Illinois 3 Mun-H-Center, Department of Odontology, The Sahlgrenska Academy at Go¨teborg University, Go¨teborg, Sweden 4 Child and Adolescent Psychiatry, The Sahlgrenska Academy at Go¨teborg University, Go¨teborg, Sweden 5 Department of Pediatrics, Skaraborg Hospital, Sko¨ude, Sweden 6 Department of Pediatrics, The Sahlgrenska Academy at Go¨teborg University, Go¨teborg, Sweden 7 Department of Otorhinolaryngology, Head and Neck Surgery, The Sahlgrenska Academy at Go¨teborg University, Go¨teborg, Sweden 2
Received 26 May 2006; Accepted 11 February 2007
Swedish patients with the oculo-auriculo-vertebral (OAV) spectrum participated in a prospective multidisciplinary investigation. The aims of the study were to describe their systemic and functional defects, especially autism spectrum disorders, and to search for possible etiologic risk factors. Available medical records were studied and the mothers answered a questionnaire on history of prenatal events. A clinical examination evaluating systemic findings, vision, hearing, speech, oral and swallowing function, and neuropsychiatric function, especially autism, was made. Eighteen patients, (11 males, 7 females) aged 8 months to 17 years with OAV were studied. Most frequent systemic malformations included, ear abnormalities (100%), ocular malformations (72%), vertebral deformities (67%), cerebral anomalies (50%), and congenital heart defects (33%). Functional defects
consisted of hearing impairment (83%), visual impairment (28%), both visual and hearing impairment (28%), difficulties in feeding/eating (50%), speech (53%), mental retardation (39%), and severe autistic symptoms (11%). Three children were born following assisted fertilization (two intracytoplasmatic sperm injection, one in vitro fertilization), two mothers reported early bleedings, and six (33%) mothers had smoked during pregnancy. ß 2007 Wiley-Liss, Inc.
Key words: Goldenhar syndrome; oculo-auriculo-vertebral (OAV) spectrum; autism spectrum disorder; in vitro fertilization; intracytoplasmatic sperm injection (ICSI); embryonic development
¨ mland K, Miller M, Sjo ¨ green L, Johansson M, Ekman Joelsson B-M, Billstedt E, How to cite this article: Stro ¨ m G. 2007. Oculo-auriculo-vertebral Gillberg C, Danielsson S, Jacobsson C, Andersson-Norinder J, Granstro spectrum: Associated anomalies, functional deficits and possible developmental risk factors. Am J Med Genet Part A 143A:1317–1325.
INTRODUCTION
Branchial arch disorders comprise a great variety of developmental anomalies. Hemifacial microsomia is among the more common conditions of the field, affecting primary aural, oral and mandibular development. It usually appears unilaterally but may be bilateral and varies from mild to severe with usually one side more severely affected than the other. Goldenhar [1952] described a variant of hemifacial microsomia in reporting more than 30 patients with a combination of epibulbar dermoids, lipodermoids, preauricular skin tags and fistula and
dysostosis of the mandible and face. Later upper lid coloboma, facial and vertebral anomalies were added as part of the syndrome [Gorlin et al., 1963]. The condition has proved to be extremely complex and heterogeneous. When the anomalies are man-
*Correspondence to: Kerstin Stromland, The Sahlgrenska Academy at Go¨teborg University, Department of Ophthalmology Department of Pediatric Ophthalmology, The Queen Silvia Children’s Hospital, SE 416 85 Go¨teborg, Sweden. E-mail:
[email protected] DOI 10.1002/ajmg.a.31769
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a ¨ MLAND ET AL. STRO
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ifested in the eyes, ears and vertebrae the term oculo-auriculo-vertebral (OAV) spectrum is often used [Gorlin et al., 2001]. In this study OAV was used as an overarching term. The prevalence of Goldenhar syndrome (GS) is difficult to estimate and varies in the reports. Grabb [1965] estimated the frequency of OAV to 1/5600 births, similar to Gorlin et al. [2001]. Most cases are sporadic, but familial instances have been observed [Rollnick and Kaye, 1983]. Similar findings as those that are characteristic for GS have been reported after the use of thalidomide [Miehlke and Partsch, 1963; Stro¨mland and Miller, 1993], primidone [Gustavsson and Cheen, 1985] and retinoic acid [Lammer et al., 1985] and in diabetic embryopathy [Grix, 1982; Wang et al., 2002]. Several chromosomal anomalies have been found with similar facial phenotypes as in OAV such as trisomy 7 mosaicism [Hodes et al., 1981], trisomy 9 mosaicism [Wilson and Barr, 1983], del (18q), del (22q) [Herman et al., 1988], dup (22q) [Hathout et al., 1998], mosaic trisomy 22 [Pridjian et al., 1995] and unbalanced (5p;8p) translocation [Josifova et al., 2004]. Autism and autistic-like features in patients with GS have been described previously [Jure et al., 1991; Landgren et al., 1992; Barton and Volkmar, 1998]. Estimates of mental retardation in OAV mostly ranged from 5 to 15% [Gorlin et al., 2001]. The purpose of the present study was to survey the systemic and functional defects in a group of Swedish patients with characteristics of OAV spectrum with a multidisciplinary team. Special attention was given to associated birth defects in OAV and functional defects. Another goal of the study was to investigate possible etiologic risk factors involved in this syndrome complex.
from the study because one also had CHARGE association and one had Down syndrome. The Ethics Committee at the Medical Faculty, The Sahlgrenska Academy at Go¨teborg University, Go¨teborg, Sweden, approved the study. Informed consent was obtained from the parents of all children participating in the study.
SUBJECTS
Ophthalmology
An invitation to refer patients with GS or OAV was sent out to Swedish physicians and other professionals dealing with this group of patients through their specialties and through advertisement in the Journal of the Swedish Medical Association. The patients were referred for GS, OAV or hemifacial microsomia. For inclusion in the study the patient had to have malformations in at least two of four areas i.e. oro-cranio-facial, ocular, auricular, and vertebral. Eighteen patients, 11 males, 7 females, eight months to 17 years old, met the criteria and participated in the study. Eight children were patients at the eye department of The Queen Silvia Children’s Hospital, where the study was performed and 10 were referred by pediatricians mostly working at rehabilitation units in different parts of Sweden. Five patients had symptoms from four areas, 12 from three and one from two areas (Table I). Two children had signs characteristic of OAV but were excluded
Depending on the mental capacity and age of the patients an ophthalmologic examination was made that included evaluation of visual function, ocular structures and ocular motility and examination of anterior and posterior segments of the eye. Visual impairment was defined as a visual acuity 0.3 (20/ 60) according to the definitions of the World Health Organization.
METHODS
A multidisciplinary team representing pediatrics with a focus on cardiology, ophthalmology, otolaryngology, dentistry, speech pathology, neuropsychiatry and neuropsychology examined the patients. Data were collected from medical records at maternal health care units, delivery units, hospitals, and dental clinics, and from interviews with the patients and their parents. The mothers completed a questionnaire on history of diseases, bleedings, use of drugs, alcohol, and smoking during pregnancy. Some patients had previously undergone radiological imaging and laboratory tests; no such tests were performed at the time of examination. A pediatric neuroradiologist (OF) reviewed films from magnetic resonance imaging (MRI) and/or computerized tomography (CT) of the brain, performed before the diagnostic study. Pediatrics
A pediatric examination was performed on each patent. Weight, length, and head circumference were recorded. The ability to walk, gross neurologic function, cardiopulmonary status, and investigation of genital anomalies was assessed.
Otolaryngology
External ear malformations including ear tags and fistulae were diagnosed by clinical examination and the ear abnormalities were graded according to Meurman [1957]. Ear canal, middle ear and inner ear malformations were diagnosed by using earlier taken CT or MRI scans, and classified according to Altman [1955] and Cremers et al. [1984]. Hearing loss was assessed by air and bone conduction audiometry and defined as being either of conductive type, sensor-
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
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OCULO-AURICULO-VERTEBRAL SPECTRUM TABLE I. Systemic Anomalies, Functional Deficits and Assisted Reproductive Technique (ART) in 18 Swedish Patients with OAV
Systemic anomalies Oro-cranio-facial Microsomia Macrostomia Cleft lip/palate/uvula Facial nerve weakness Ocular Lipodermal dermoid Epibulbar dermoid Microphthtalmus Auricular External ear Middle ear Inner ear Vertebral Cervical spine Scoliosis Other Cardiovascular Respiratory system Gastrointestinal Genito-urinary Brain Limb Functional deficits Developmental delay Autism spectrum disorder Impaired vision Sensorineural hearing loss Conductive hearing loss Impaired speech Dysphagia ART IVF ICSI
1
2
3
4
5
6
7
8
B B
B B
B
U
U
U U þ þ
U U þ þ
U
U U U U
U
B B
U U B B
U
U
þ
B B U
B U U B
þ
þ þ
9
10
11
12
13
14
15
16
17
18
U
U
U
U
U
U
U
U U
þ þ
þ þ
þ þ
B þ
B
U
B U ne
U U ne
þ þ
þ U U U B U ne þ
B ne þ þ
B B U B ne
B ne B
þ
þ
þ
þ þ
þ
þ þ þ B U þ
B ne þ
B þ þ
þ þ þ
þ þ
þ þ
B U ne
U U
U U ne
U ne U
B U U þ
þ
þ
þ þ
þ þ þ
þ
þ
þ
þ
þ
þ
þ U þ þ
U
B
þ
þ þ
U U
B B
þ þ
þ
U
B B
þ þ þ
þ þ
þ
B þ þ
B þ þ
þ B B þ þ
ne þ
B B þ
B B
B U ne
þ
þ þ
þ
IVF, in vitro fertilization; ICSI, Intracytoplasmatic sperm injection; U, unilateral; B,bilateral; ne, not evaluated.
ineural or combined hearing loss. Hearing in the youngest patients was evaluated by brain stem audiometry, and later evaluated by standard audiometry. Odontology, Speech Pathology
A team of dentists and a speech language pathologist made the orofacial examination. The Mun-H-Center Observation Chart [Andersson-Norinder, 1996] was used for recording orofacial morphology, odontology, and oral motor function, and speech. Photographs and video recordings were used to document facial expression, tongue motility and speech. Neuropsychiatry
Autism and other autistic spectrum disorders are defined by specific abnormalities in reciprocal social interaction, communication, and unusual interests, and behaviors. The focus of the neuropsychiatric assessment was to identify combinations of distur-
bances in these domains and to assess the level of intellectual functioning. Autistic symptoms were scrutinized by utilizing the autistic behavior checklist [ABC; Krug et al., 1980], the childhood autism rating scale [CARS; Schopler et al., 1980], the ADI-R [autism diagnostic interview-revised; Lord et al., 1994], the DSM-III-R checklist for autistic disorder [American Psychiatric Association, 1987] and the DSM-IV checklist for autistic disorder [American Psychiatric Association, 1994]. Childhood autism (CA)/autistic disorder (AD) was diagnosed in participants who clinically met the DSM-III-R- and the DSM-IV criteria for AD as well as the ADI-R algorithm criteria for CA. Autistic-like condition (ALC)/Atypical autism was diagnosed in patients showing severe impairments in social interaction and restricted communication and/ or behavior, meeting six or seven of the DSM-III-R symptom criteria and five of the DSM-IV symptom criteria for AD. The cognitive level was assessed with the Wechsler intelligence scale for children [WISC-III; Wechsler, 1992], Griffiths developmental scales [Griffiths, 1970] or the Vineland adaptive behavior scales [Sparrow et al., 1984].
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a ¨ MLAND ET AL. STRO
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RESULTS Pediatrics
There were four twin pregnancies (Patients 1, 2, 4, and 13) (Fig. 1), four children were born in gestational weeks 31–36 and 14 had a gestational age between 37 and 42 weeks. The age of the mothers ranged from 21 to 38 years (median and mean age 29 years) and of the fathers from 22 to 54 years (median age 30 years, mean age 32 years). Most (15) children were of normal size at birth (weight between 2500 and 4500 g), three had a birth weight less than 3 S.D. At follow-up 11 children had a normal growth while 7 had short stature (height < 2 S.D.). The head circumference was normal at follow-up in 15 children, less than
