Marilyn T. Miller

Autism in thalidomide embryopathy : a population study

Of a population of 100 Swedish thalidomide embryopathy cases, at least four met full criteria for DSM‐III‐R autistic disorder and ICD‐10 childhood autism. Thalidomide embryopathy of the kind encountered in these cases affects fetal development early in pregnancy, probably on days 20 to 24 after conception. It is argued that the possible association of thalidomide embryopathy with autism may shed some light on the issue of which neural circuitries may be involved in autism pathogenesis.

Teratogen update: thalidomide: a review, with a focus on ocular findings and new potential uses

Thalidomide (a-[N-phthalmido]-glutarimide) was synthesized in 1954, in what was then West Germany, by Chemie Grunenthal under the brand name of Contergan and was subsequently licensed in 46 other countries worldwide, covering all continents. It is an odorless white crystalline compound with low solubility in water (McBride, ’77; Stirling et al., ’97). A number of pharmaceutical companies manufactured thalidomide in various concentrations under several trade names (Stirling et al., ’97).Advertisements for the drug claimed that it was helpful in treating anxiety, insomnia, gastritis, and tension and that it was safe and harmless for pregnant women (Lenz, ’88). Additionally, it was an effective antiemetic in pregnancy (McBride, ’77). Thalidomide was first marketed in Germany in October 1957 as an effective, safe, inexpensive sedative, and production in that country reached 14.58 tons by 1960 (Zwingenberger and Wendt, ’96). A liquid form was available for children, and some compounds were sold without prescriptions (Stirling et al., ’97). Routine screening tests found thalidomide to be nontoxic in rodents, and therefore its potent teratogenicity in humans and higher mammals was not anticipated (Brent and Holmes, ’88). In the early 1960s an increasing number of infants were born with hypoplastic limb defects (Lenz,’85). In fall 1961, Lenz, noting these congenital malformations in the German population, suggested a possible correlation with thalidomide taken during pregnancy. He reported his observations at meetings and in the medical literature (Lenz,’61a,b,’62; Lenz and Knapp, ’62). Similar observations were made in England (Smithells, ’62) and Australia (McBride, ’61). Within a few months of the initially reported cases, the drug was withdrawn from commercial sale by Grunenthal (November 1961), and 9 months later was taken off the market in Japan. It was withdrawn from Great Britain in December 1961 (Kida, ’87). The potent teratogenicity appropriately suppressed other uses of thalidomide, such as for anti-inflammatory effects (Somers, ’60, Miller et al., ’60). The U.S. Food and Drug Administration (FDA) had not approved the drug for unrestricted use because of concerns (primarily about possible peripheral neuropathy) raised by Francis Kelsey, an FDA physician. Thus the number of cases of thalidomide embryopathy in the United States was small (Kelsey, ’88). The teratogenic effects of thalidomide contributed to the passage of new regulatory legislation for pharmaceuticals (Stirling et al.,’97). There are many reviews in the literature of various aspects of the thalidomide story (McBride, ’77; Fraser, ’88; Kelsey, ’88; Lenz, ’88; Warkany, ’88; Lenz, ’88).

Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review

Autism is a complex developmental disorder without an established single etiology but with significant contributions from genetic studies, functional research, and neuropsychiatric and neuroradiologic investigations. The purpose of this paper is to review the findings in five studies involving individuals manifesting the characteristic findings of autism spectrum disorder associated with malformations and dysfunctions known to result from early embryogenic defects. These investigations include two associated with teratogens (thalidomide embryopathy, Möbius sequence with misoprostol) and three (most Möbius sequence cases, CHARGE association, Goldenhar syndrome) with no known etiology.

AUTISM AND MÖBIUS SEQUENCE An exploratory study of children in northeastern Brazil

The psychiatric examination was performed with diagnostic instruments for autism (DSM-IV and Childhood Autism Rating Scale-CARS) in 23 children with Möbius sequence. From the 23 patients studied with Möbius sequence, five (26.1%) met the diagnostic criteria for infantile autism according DSM-IV and two (8.6%), under two years old, showed autistic-like behavior. The scores for six children were compatible to severe autism symptoms according CARS and one child met the criteria for moderate autism symptoms. Among five children with autism, three (60%) had positive history of misoprostol exposure during the first trimester of pregnancy and from two cases autistic-like, one (50%) had positive history of misoprostol exposure during pregnancy. According to our data, this is the first report of Möbius sequence with autism and positive history of misoprostol use during pregnancy.

Oculo-auriculo-vertebral spectrum: associated anomalies, functional deficits and possible developmental risk factors.

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.

Autistic spectrum disorders in Möbius sequence: a comprehensive study of 25 individuals

The prevalence of autistic disorder was analysed in 25 individuals with Möbius sequence, a disorder with brain-stem dysfunction. The sample consisted of 18 males and seven females (20 participants were aged 2 to 22 years, and five were aged 1, 19 and 23 months, and 55 years old). Participants were recruited after a nationwide call and were part of a multidisciplinary study of individuals with Möbius sequence. They were given a meticulous neuropsychiatric examination including standardized autism diagnostic interviews. Ten individuals had an autistic spectrum disorder. Six of these met all diagnostic criteria for autism. In 23 individuals cognitive development could be assessed. Eight of those 23 patients had clear learning disability and six individuals were functioning in the normal but subaverage range. Autistic spectrum disorder and learning disability occurred in more than a third of the examined patients. Considering the hospital-based nature of the sample, these findings may be overestimates. Nevertheless, awareness of this coexistence is important in the diagnosis and habilitation care of children with Möbius sequence. Moreover, the results provide further support for the notion of a subgroup of autistic spectrum disorders being caused by first trimester brain-stem damage.

The Möbius sequence: A relook

BACKGROUND The constellations of findings often referred to as Mobius syndrome might be better described as Mobius sequence, because the term sequence defines a cascade of secondary events after an embryonic insult from heterogeneous causes. Classic clinical findings include evidence of sixth and seventh cranial nerve involvement, often with associated malformations of limbs, craniofacial structures, and other cranial nerves. METHODS A prospective study was undertaken in Sweden of 25 patients who showed characteristic findings of Mobius sequence. RESULTS Of the patients who did not have strabismus surgery, 10 patients had straight eyes in the primary position, 7 had esotropia, 2 had exotropia, and 1 had hypertropia. All had significant limitation of abduction, except 1 patient with exotropia who showed minimal underaction on abduction but a large limitation of adduction. In the description in these early cases, some patients manifested a clinical pattern resembling a horizontal gaze paresis. Narrowing of the palpebral fissure on adduction similar to that seen in Duane syndrome was observed in a few cases. Two patients had ptosis. Nineteen patients had diminished facial expression bilaterally, often asymmetric, and 6 cases appeared to be unilateral. Seven patients had abnormal tearing. Associated systemic findings included Poland anomaly (2), club feet or other limb anomalies (8), micrognathia (8), tongue malformations (17), cleft palate (5), and speech problems (18). An unusual finding was autism syndrome (6) or autism-like syndrome (1). CONCLUSIONS The associated findings in Mobius sequence may give further clues to the location and timing of the developmental disturbance. The wide range of ocular motility patterns suggests that the previous concept of a lesion solely in the sixth nerve nucleus is an inadequate explanation for these findings.

Thalidomide embryopathy: Revisited 27 years later

Abstract A prospective ophthalmological study was done in 86 out of a total of 100 Swedes with established thalidomide embryopathy. Forty‐six (54%) of all examined individuals had eye findings, which made the eye the second most commonly affected organ in thalidomide embryopathy only surpassed by upper limbs (81%). Forty‐three patients (50%) had ocular motility defects, mostly incomitant strabismus. Facial palsy and abnormal lacrimation each occurred in 17 (20%) individuals. One patient had coloboma of the uvea and optic disc and another two had coloboma of the optic disc. Infrequent anomalies were microphthalmos, congenital glaucoma, lipodermoid, and large refractive errors. The observed ocular motility defects, facial palsy and abnormal lacrimation occurred with early induced defects in thalidomide embryopathy, but not with isolated late occurring anomalies. This suggests that thalidomide exerts its effects on the development of these structures early in the teratogenic period, probably mainly during the fourth week of development.

Progressive Hemifacial Atrophy (Parry-Romberg Disease)

Hemifacial atrophy (Parry-Romberg syndrome) is characterized by slowly progressive atrophy of one side of the face, primarily involving the subcutaneous tissue and fat. The onset is usually in the first two decades. Ophthalmic involvement is common; the most frequent abnormality is progressive endophthalmos with subsequent changes in the palpebral fissure. Pupillary disturbances, heterochromia, uveitis, and restrictive strabismus have also been frequently reported. We describe six cases that manifest a wide spectrum of ocular and systemic findings. They are noteworthy in that all exhibit pigmentary disturbances of the ocular fundus, a finding rarely reported. Another unusual ocular manifestation in one patient was an acquired partial third nerve palsy on the unaffected side.

Parameters of Care for Craniosynostosis

Background A multidisciplinary meeting was held from March 4 to 6, 2010, in Atlanta, Georgia, entitled “Craniosynostosis: Developing Parameters for Diagnosis, Treatment, and Management.” The goal of this meeting was to create parameters of care for individuals with craniosynostosis. Methods Fifty-two conference attendees represented a broad range of expertise, including anesthesiology, craniofacial surgery, dentistry, genetics, hand surgery, neurosurgery, nursing, ophthalmology, oral and maxillofacial surgery, orthodontics, otolaryngology, pediatrics, psychology, public health, radiology, and speech-language pathology. These attendees also represented 16 professional societies and peer-reviewed journals. The current state of knowledge related to each discipline was reviewed. Based on areas of expertise, four breakout groups were created to reach a consensus and draft specialty-specific parameters of care based on the literature or, in the absence of literature, broad clinical experience. In an iterative manner, the specialty-specific draft recommendations were presented to all conference attendees. Participants discussed the recommendations in multidisciplinary groups to facilitate exchange and consensus across disciplines. After the conference, a pediatric intensivist and social worker reviewed the recommendations. Results Consensus was reached among the 52 conference attendees and two post hoc reviewers. Longitudinal parameters of care were developed for the diagnosis, treatment, and management of craniosynostosis in each of the 18 specialty areas of care from prenatal evaluation to adulthood. Conclusions To our knowledge, this is the first multidisciplinary effort to develop parameters of care for craniosynostosis. These parameters were designed to help facilitate the development of educational programs for the patient, families, and health-care professionals; stimulate the creation of a national database and registry to promote research, especially in the area of outcome studies; improve credentialing of interdisciplinary craniofacial clinical teams; and improve the availability of health insurance coverage for all individuals with craniosynostosis.