Catharina Jacobsson

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.

Development of speech, feeding, eating, and facial expression in Möbius sequence.

OBJECTIVE Möbius sequence is a rare congenital disorder with the primary diagnostic criteria of congenital facial and abducens nerve palsy. Involvement from other cranial nerves is common. Orofacial anomalies and limb malformations may be associated with the disorder. Mental retardation and autism have been reported in some. The aim of this study was to describe orofacial dysfunction observed in a prospective, multidisciplinary study of individuals with Möbius sequence. METHODS Twenty-five patients with Möbius sequence, aged 2 months to 54 years, participated in the study. Clinical observations by different medical specialists were collected in an established database. Dentists and a speech pathologist made the orofacial examination. The parents or the patient described orofacial function and dysfunction through interviews and a questionnaire. RESULTS Bilateral facial palsy was observed in 16 patients, unilateral palsy in 9. Observed orofacial anomalies were tongue dysfunction (16), micrognatia (8), microglossia (7), cleft palate (4), and cleft lip (1). Seventeen had speech problems, 16 reported feeding difficulties in infancy, 14 eating problems, and 8 drooling. CONCLUSIONS Orofacial problems are common in Möbius sequence and have a significant impact on the quality of life for the patient and for the whole family. Early intervention by a speech pathologist and a paediatric dentist should be undertaken to improve orofacial function and symptoms. Plastic surgery, oral motor training, facial massage, speech therapy, and orthodontic treatment are some of the therapy methods that can be considered.

CHARGE association in Sweden: Malformations and functional deficits

CHARGE association (CA) consists of a non‐random association of ocular coloboma (C), heart anomaly (H), atresia of choanae (A), retarded growth and/or development (R), genital hypoplasia (G), and ear anomalies and/or hearing impairment (E). A prospective multidisciplinary study of 31 Swedish patients with CA was undertaken in order to describe the associated malformations and functional deficits, find possible etiological factors and identify critical time periods for the maldevelopment. The clinical files were analyzed, the mothers answered a questionnaire on history of prenatal events, and a clinical evaluation of systemic findings, vision, hearing, balance, speech, oral and swallowing function, and neuro‐psychiatric function, especially autism, was performed. The most frequent physical abnormalities affected ears (90%), eyes (90%), brain (61%), heart (52%), retarded growth (48%), genitals (38%), choanae (35%), and facial nerve (32%). Sixty‐one percent of the patients were visually impaired or blind, and 74% had hearing loss or deafness. Problems in balance, speech, and eating were common. Forty percent of the patients had autism/atypical autism, and 82% had developmental delay. Three children were born following assisted fertilization and two mothers had diabetes. The mothers reported infections, bleedings, and drug use during pregnancy. Analysis of possible critical time periods suggested that most malformations were produced early in pregnancy, mainly during post conceptual weeks 4, 5, and 6. A multidisciplinary approach is essential in the assessment and management of CA.

CLINICAL APPEARANCE OF SPONTANEOUS AND INDUCED FIRST AND SECOND BRANCHIAL ARCH SYNDROMES

The clinical appearance was investigated of 29 patients with mandibulofacial dysostosis, 26 with hemifacial microsomia, and seven with thalidomide-induced malformations affecting derivatives of the first and second branchial arches. Malformations of the external ear, ear canal, middle ear, zygoma, maxilla, mandible, and lower eye lid were prominent features of the syndromes. Facial nerve and 6th cranial nerve paralysis as well as anophthalmia or microphthalmia were seen only in patients with hemifacial microsomia and in the thalidomide-induced syndrome. We compared the clinical results with those in an animal model in which an induced first and second branchial arch syndrome depends on disturbed migration of neural crest cell during early embryogenesis. The critical time for a similar process in humans would be between the 20th and 29th days of pregnancy.

Effects of Vitamin B6 on Beta-Aminoproprionitrile–Induced Palatal Cleft Formation in the Rat

OBJECTIVE This study was conducted to evaluate the effects of beta-aminoproprionitrile and vitamin B6 on palatal clefting. METHOD In four groups of pregnant Sprague-Dawley rats, beta-aminoproprionitrile (BAPN; 600 mg/kg b.w.) was given by gavage on embryonal day 15, 7 hours to induce palatal clefts. Vitamin B6 (10 mg/kg b.w., IM) was given twice on embryonal day 14, 7 hours and on day 15, 7 hours. The possibility that the foods content of vitamin B6 affected the results was also tested. Palatal cleft formation was divided into four different grades, ranging from no cleft formation to total cleft formation. RESULTS/CONCLUSION It was found that BAPN induces cleft palate in rat fetuses and that this defect can be prevented both in number and severity by administration of vitamin B6 before and simultaneously with BAPN.

Enzyme histochemical analysis of craniofacial malformations induced by retinoids.

Craniofacial malformations were induced in 256 embryos from 32 pregnant rats by a single intraperitoneal injection of 10 mg/kg etretinate at 8.5 days gestation. The litters developed several malformations including microtia, low set and dorsally placed outer ears, defective middle ear ossicles, short cochleas, defectively differentiated Meckels cartilages, micrognathia, rudimentary malar bones, lateral facial clefts, fistulas, and skin tags, all of which tissues are derivatives of the first and second branchial arches. The teratogenically induced syndrome shows similarities to the mandibulofacial dysostosis syndrome in man. The defects were accompanied by a change in the histochemical differentiation and location of various enzymes in the craniofacial tissues.

Diagnosis of Induced Cleft Palate in Rats from Defective Patterns of Differentiation of Isoenzymes

Cleft palate was induced in 420 embryos of Sprague-Dawley rats with a single oral dose of 600 mg/kg beta-aminoproprionitrile (BAPN) on embryonal day 15, 7 hours. The cleft palate was accompanied by a pathological differentiation pattern of various isoenzymes in palatal shelves. These isoenzymes could be detected in amniotic fluid from the 16th to the 20th days of pregnancy when they also had a pathological differentiation pattern. We conclude that teratogenically induced cleft palate in rats is accompanied by a pathological differentiation pattern that can be traced by determination of isoenzymes in the palatal shelves as well as in amniotic fluid.

Etretinate-induced malformation of the first two branchial arches : Differential staining and microdissection study of embryonic cartilage

Malformations of the cranial base, temporal bone and middle ear were induced in the offspring of Sprague-Dawley rats by a single intraperitoneal injection of 10-30 mg/kg etretinate (Tigasone) at days 8.5-10.5 of gestation. By differential staining of the embryonic craniofacial cartilage and bone, and microdissection of the otomandibular complex, the induced malformations were studied specifically. Defective formations of Meckels cartilage and the cartilaginous skull base were found to be prominent features of the malformation. The malformation included defective middle-ear ossicles; especially the malleus and incus were fused with a shorter than normal long process and manubrium. In conjunction with the distal part of Meckels cartilage, mandibular micrognathia was observed. All of the malformed tissues are derivatives of the first and second branchial arches. The teratogenically induced defects in the rat embryos show some similarities to the clinical syndromes of the first and second branchial arches in man.