Somatosensory and auditory processing in opioid-exposed newborns with neonatal abstinence syndrome: a magnetoencephalographic approach.

OBJECTIVE: Opioid exposure during pregnancy is a potential risk factor for the developing central nervous system of the fetus. We studied evoked responses in buprenorphine-exposed newborns who displayed neonatal abstinence syndrome (NAS) to elucidate the possible alterations in functioning of the somatosensory and auditory systems. METHODS: We compared somatosensory (SEFs) and auditory evoked magnetic fields (AEFs), recorded with magnetoencephalography (MEG), of 11 prenatally buprenorphine-exposed newborns with those of 12 healthy newborns. Peak latencies, source strength and location of SEFs or AEFs were recorded. RESULTS: AEFs were present in all buprenorphine-exposed newborns without significant differences from those of healthy newborns. In contrast, though no group level differences in SEFs existed, at individual level the response deviated from the typical neonatal morphology in four buprenorphine-exposed newborns. CONCLUSIONS: Although buprenorphine exposure during pregnancy does not seem to cause constant deficiencies in somatosensory or auditory processing, in some newborns the typical development of somatosensory networks may be - at least transiently - disrupted.

Dental health of young children prenatally exposed to buprenorphine. A concern of child neglect?

PURPOSE: To study the oral health and dental neglect of prenatally buprenorphine-exposed 3-year-old children. METHODS: The study consisted of 51 children who as newborns tested positive for buprenorphine in a urine screen. The control group comprised 68 children previously unexposed to narcotics. The dentist examined the children and interviewed their guardians. RESULTS: Buprenorphine-exposed children exhibited significantly more early childhood caries than did the control group. Caries indices, the number of decayed, missing and filled teeth or tooth surfaces and decayed teeth were greater in the buprenorphine-exposed children than the control children (p = 0.004, p = 0.004, p = 0.001, respectively). In the buprenorphine group, more children showed visible plaque (p = 0.003) and fewer children were caries-free (p = 0.009) than in the control group. The control children's teeth were also brushed more often than the buprenorphine-exposed children's teeth (p = 0.001) and the parents were more involved in their children's tooth brushing than were those in the buprenorphine-exposed group (p = 0.035). CONCLUSIONS: More caries and dental neglect were found in buprenorphine-exposed children than in controls. These findings highlight the importance of routine dental appointments, caries screening and preventive care for children in substance-abusing families.

Brain magnetic resonance imaging of infants exposed prenatally to buprenorphine.

PURPOSE: To evaluate the brains of newborns exposed to buprenorphine prenatally. MATERIAL AND METHODS: Seven neonates followed up antenatally in connection with their mothers' buprenorphine replacement therapy underwent 1.5 T magnetic resonance imaging (MRI) of the brain before the age of 2 months. The infants were born to heavy drug abusers. Four mothers were hepatitis C positive, and all were HIV negative. All mothers smoked tobacco and used benzodiazepines. All pregnancies were full term, and no perinatal asphyxia occurred. All but one neonate had abstinence syndrome and needed morphine replacement therapy. RESULTS: Neither structural abnormalities nor abnormalities in signal intensity were recorded. CONCLUSION: Buprenorphine replacement therapy does not seem to cause any major structural abnormalities of the brain, and it may prevent known hypoxic-ischemic brain changes resulting from uncontrolled drug abuse. Longitudinal studies are needed to assess possible abnormalities in the brain maturation process.

Craniofacial features in Cohen syndrome: an anthropometric and cephalometric analysis of 14 patients.

Cohen syndrome (Mendelian Inheritance in Man [MIM] no. 216550) is a rare, autosomal-recessive inherited disorder with mental retardation and a typical appearance. The condition is relatively common in Finland where 35 patients have been diagnosed. We studied 22 patients in detail, obtaining anthropometric measurements of the head and face, and cephalometric radiographs of 14 patients (14-57 years of age). Measurements of patients were compared to population norms and matched controls. Anthropometric analysis confirmed and quantified the previously described syndrome features: small head size [-4 standard deviations (SD)], with varying cephalic index. Width of the upper face was close to normal, but width of the lower face was small. Philtrum length was shorter than in healthy controls (p = 0.0039 in females and p = 0.0014 in males). The measurements from standardized radiographs revealed short cranial base dimensions (-2.2 and -2.6 SD), but normal cranial base angles. Prognathism of jaws was within normal limits. Reduced head size (microcephaly), short philtrum and small cranial base dimensions are essential features in Cohen syndrome. In addition, most patients had forward-inclined upper incisors and maxillary prognathia. We conclude that exact measurements mostly confirmed the Cohen syndrome description based previously on clinical impression.

Cohen syndrome: essential features, natural history, and heterogeneity.

This article elucidates the clinical picture in Cohen syndrome (MIM 216550), an autosomal recessive disorder that is overrepresented in Finland. The diagnosis is based on the typical clinical picture: nonprogressive psychomotor retardation, motor clumsiness and microcephaly, typical facial features, childhood hypotonia and hyperextensibility of the joints, ophthalmologic findings of retinochoroidal dystrophy and myopia in patients over 5 years of age, and granulocytopenia. In a nationwide study, 29 Finnish patients were investigated. Magnetic resonance images of the brain with quantitative structure analyses revealed a relatively enlarged corpus callosum (CC). The youngest patients had normal EEGs, while all others had low-voltage EEGs. Of the patients, 22% had profound, 61% severe, 6% moderate, and 11% mild retardation. In an adaptive behavior scale (AAMD), patients had high scores in the positive domains (self-direction, responsibility, and socialization), whereas maladaptive behavior was almost lacking. Only the youngest patients had unimpaired visual function. Vision started to deteriorate early but slowly. Progressive myopia and retinochoroidal dystrophy were found in all of the patients over 5 years of age. All of the patients had isolated granulocytopenia. The heart anatomy was normal. However, decreased left ventricular function with advancing age was found. No significant endocrine abnormalities were discovered. Fingers were slender but short, with a typical metacarpophalangeal pattern profile. The manifestations vary at different ages. The Finnish Cohen patients are clinically highly homogeneous, their disease gene being located on chromosome 8. Heterogeneity probably exists among other patients claimed to have Cohen syndrome.

Ophthalmologic findings in Cohen syndrome. A long-term follow-up.

OBJECTIVE: To determine the nature and course of ophthalmologic abnormalities and their clinical significance in Cohen syndrome. STUDY DESIGN: Observational case series. PARTICIPANTS: Twenty-two Cohen syndrome patients aged 2 to 57 years were examined, and a retrospective review of ophthalmologic records was carried out for 14 of them. All but one were part of the Finnish study of refined mapping of the Cohen syndrome gene by linkage disequilibrium in chromosome 8. MAIN OUTCOME MEASURES: Visual acuity (VA), cycloplegic refraction, biomicroscopy, lens opacitometry, ophthalmoscopy, and fundus photography. RESULTS: With the exception of the two youngest patients, all had symptoms such as nyctalopia, impaired vision, and visual field loss. Progressive, often high-grade myopia, astigmatism, and retinochoroidal dystrophy resembling retinitis pigmentosa occurred in all, except for the youngest patients. The earliest fundus changes were pale disc and pale fundus with or without pigment granularity, followed by narrowed vessels, pigment clumps, and bone spiculelike pigment accumulations by 10 to 20 years of age. Pigment deposits increased and approached the posterior pole by 35 to 40 years of age. Patients more than 45 years of age had severe retinochoroidal atrophy. A bull's-eye macula was seen in most patients. Teenagers had peripheral lens opacities, and young adults had early nuclear sclerosis confirmed by lens opacitometry. Older patients also had posterior subcapsular cataracts, iris atrophy, and iridophacodonesis. Vision started to deteriorate at the age of 6 to 10 years, but remained relatively good (VA 0.5-0.1) in most patients until 30 and, in one case, 46 years of age. Older patients were severely visually handicapped (VA hand motion to light perception), but none were completely blind. CONCLUSIONS: Progressive myopia and retinochoroidal dystrophy are essential features in Cohen syndrome and, together with early lens opacities, lead to deterioration of vision. Cohen syndrome patients need careful ophthalmologic follow-up at all ages. Nyctalopia and restricted visual fields should be considered when planning the patient's daily activities.

Neurological and psychological findings in patients with Cohen syndrome: a study of 18 patients aged 11 months to 57 years.

Our purpose was to perform the first systematic neurological, neurophysiological and psychological study of 18 patients with Cohen syndrome (MIM no 216550), aged 11 months to 57 years (median 27 years). All the patients had the essential features of this syndrome, i.e., typical facial and structural findings, mental retardation, microcephaly, ophthalmologic symptoms, granulocytopenia and a cheerful psychic disposition. Children with the syndrome were considered normal at birth, but upwards of 6 to 12 months, psychomotor retardation became obvious. The first symptoms were microcephaly, which manifested itself by the age of 6 months to 1 year, as well as hypotonia and delayed developmental milestones. Cohen children learned to walk at 2 to 5 years of age. Language development varied markedly. Neurological symptoms did not progress. All patients had normal EMGs. The three youngest (aged 11 months, 3 and 5 years) had normal EEGs, whereas the remainder had low-voltage EEGs. No irritative spikes or epileptoformic foci were found. Nine patients had quick beta transients. Of the 18 patients examined, 4 were profoundly, 11 severely, 1 moderately and 2 mildly retarded. On the AADM scale, Cohen patients had high scores in the positive domains, viz., self-direction, responsibility and socialisation. Maladaptive behaviour, on the other hand, was almost completely absent, except for stereotyped behaviours and odd mannerisms. Withdrawal, sexually aberrant behaviour, untrustworthy and rebellious behaviour as well as antisocial behaviour were rare. These findings are consistent with the cheerful and sociable disposition characteristic of those with Cohen syndrome.

Cohen syndrome: evaluation of its cardiac, endocrine and radiological features.

Cohen syndrome (MIM no. 216550) is an autosomal recessive disorder with a typical clinical picture. Since the first report, most publications have represented single case reports. In this study, our aim was to describe cardiac, endocrine and radiological abnormalities in 22 Cohen patients of Finnish descent. Detailed investigations of the heart revealed the anatomy of the heart to be normal with no evidence for clinically significant mitral prolapse. However, a decreased left ventricular function with advancing age was identified. No significant endocrine abnormalities were found at the examination of pituitary, adrenal and thyroid function. The height was either normal or patients were moderately short (mean height standard deviation score (SDS) - 2) at all ages, associated, however, often with the marked kyphosis. Truncal obesity was seen in 4/22 patients. X-rays of the chest, lumbar and thoracic spine, long bones, ankles and metacarpophalangeal pattern profiles revealed kyphosis, scoliosis and calcaneo planovalgus as common features. Fingers of these patients were slender but short with a characteristic metacarpophalangeal pattern profile.

MRI of the brain in the Cohen syndrome: a relatively large corpus callosum in patients with mental retardation and microcephaly.

Our purpose was to perform the first systematic brain magnetic resonance imaging (MRI) study of a substantial number of Cohen syndrome (MIM n:o 216550) patients. 18 Cohen patients and 26 healthy volunteers were examined by MRI (1.0 T). All Cohen patients had essential features of this syndrome: typical facial and structural features, mental retardation, microcephaly, ophthalmologic symptoms, granulocytopenia and cheerful psychic disposition. All our patients belong to the recently published study of refined mapping of the Cohen syndrome gene by linkage disequilibrium. As visual analysis of MR images revealed an impression of a large corpus callosum (CC), quantitative analysis was performed. Sagittal diameter of the body of the CC was larger than that of controls (p = 0.02), whereas all sagittal diameters of the brain stem were markedly smaller (p < 0.0001), as was the midline internal skull surface (MISS) (p < 0.0001). The CC surface did not significantly differ from that of controls significantly. Our main finding, a relatively enlarged corpus callosum, has not previously been reported to associate with mental retardation. Though MRI alone can not confirm the diagnosis and no definite measurements can be recommended for clinical use, any clinical suspicion of this syndrome receives reinforcement through MRI: a relatively enlarged corpus callosum in a microcephalic head and normal signal intensities of the grey and white matters.

Granulocytopenia in Cohen syndrome.

Cohen syndrome is an autosomal recessive disorder characterized by mental retardation, microcephalia and typical craniofacial features, myopia and chorioretinal dystrophy. As some patients were reported to have leucopenia, we collected the haematological data of 26 Finnish Cohen patients. They all had experienced periods of isolated granulocytopenia from an early age. Granulocytopenia was mild to moderate, non-cyclic and never fatal. Most patients suffered from prolonged or repeated gingival or skin infections. We restudied 16 patients. Bone marrow examination revealed in all patients a normo- or hypercellular marrow, with a left-shifted granulopoiesis in 8/16 patients. The response to adrenaline stimulation was subnormal in 12/14 and to hydrocortisone in 8/16 patients, but administration of rhG-CSF caused granulocytosis in the three patients studied. No bone marrow malignancies were seen.

Refined mapping of the Cohen syndrome gene by linkage disequilibrium.

The Cohen syndrome is a rare autosomal recessively inherited disorder. Contrary to many case reports published elsewhere, the phenotype is uniform in Finland including nonprogressive mental and motor retardation, typical dysmorphic features, granulocytopenia and marked ophthalmological changes. By linkage analysis in five Finnish multiplex nuclear families, the COH1 locus for the Cohen syndrome was recently assigned to a 10-cM region between loci D8S270 and D8S521 on the long arm of chromosome 8. Here we present results of linkage disequilibrium and haplotype analysis in an extended panel of 16 Finnish COH1 families using new markers localized in the COH1 region. By inferring historical recombinations in conserved haplotypes the COH1 gene was assigned in the region of marker loci D8S1808, D8S1762 and D8S546. Calculations of genetic distances based on linkage disequilibrium suggest that the most likely localization of COH1 is in the immediate vicinity of marker locus D8S1762. Haplotype analysis suggests the occurrence of one main COH1 mutation and possibly one or two rare ones in Finland. This information will be useful in the positional cloning of the gene.

Periodontal findings in Cohen syndrome with chronic neutropenia.

Radiographic periodontal status and microbiological findings of periodontal pockets in subjects with Cohen syndrome are presented in this report. This hereditary disorder causes mental retardation, and neutropenia is one feature of the syndrome. Fifteen patients with Cohen syndrome and 15 controls matched for age and sex and, as far as possible, according to the degree of mental retardation were examined. Alveolar bone loss was evaluated from the panoramic radiographs. Two subgingival samples were obtained from the most affected anterior and posterior periodontal sites in each dentate subject and examined for the occurrence of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia/nigrescens, Peptostreptococcus micros, Bacteroides forsythus, and Campylobacter rectus. Subjects with Cohen syndrome had alveolar bone loss more frequently and the bone loss was more extensive (Mann-Whitney U-test: P < 0.05) than in the controls. They also harbored one or several of the putative periodontal pathogens (Mann-Whitney U-test: P < 0.001) more often than the controls. We conclude that subjects with Cohen syndrome have increased susceptibility to early periodontal breakdown which is likely to be associated with neutropenia.