The clinical utility of MRI in patients with neurodevelopmental disorders of unknown origin.

INTRODUCTION: Neuroimaging of the brain in the diagnostic work-up of patients with neurodevelopmental disorders is a matter of continuing debate. Recommendations range from performing brain imaging in all patients with neurodevelopmental disorders to performing an MRI only in those with indication on clinical examinations. Important indications for neuroimaging are head size abnormalities and focal neurological findings. METHODS: Patients with neurodevelopmental disorders of unknown origin (n = 410), referred to a specialized tertiary diagnostic center for neurodevelopmental disorders were included in a retrospective analysis. A 1-day work-up, including an MRI of the brain was performed. Studied were the: (i) yield of MRI scans of the brain and (ii) associations of specific clinical symptoms/signs with abnormal and diagnostic MRI scans. RESULTS: (i) In 30.7% of the 410 patients with neurodevelopmental disorders (n = 126), abnormal MRI scans were observed, leading to an etiological diagnosis in 5.4% of the patients (n = 22). (ii) Pyramidal disorders (P = 0.001), epilepsy (P = 0.04) and an abnormal head circumference (P = 0.02) were associated with an abnormal MRI scan. The presence of one of the following neurological symptoms/signs: movement disorders, pyramidal disorders, epilepsy, or an abnormal head circumference was associated with a diagnostic MRI scan (P < 0.001) (diagnostic MRI % in neurological versus no neurological symptoms/signs, 13.0% versus 1.9%). CONCLUSION: Neuroimaging of the brain in a tertiary care center for patients with neurodevelopmental disorders of unknown origin is useful, especially in case of neurological symptoms/signs.

Oculodentodigital dysplasia with mandibular retrognathism and absence of syndactyly: a case report with a novel mutation in the connexin 43 gene.

Oculodentodigital dysplasia (ODDD) is a rare, autosomal dominant pleiotropic disorder, caused by mutations in the Connexin 43 (Cx43 or GJA1) gene. Described here is the case of a 10-year-old girl with enamel hypoplasia, typical facies and mental delay, initially thought to be related to an unknown metabolic disorder. Careful clinical re-evaluation revealed a type of ODDD, characterised by the predominance of facial and ophthalmological involvement with mandibular retrognathism, and by the absence of cutaneous hand or foot syndactyly. A novel single-sequence variation (Nt460A>G) in exon 2, resulting in the substitution of alanine for threonine at amino acid 154, was found. These findings confirm once again the highly variable phenotypic expression caused by Cx43 mutations.

[Congenital myotonic dystrophy--the significance of a handshake]. / Congenitale myotone dystrofie--wat is er 'aan de hand'?

Three neonates, all girls, were presented immediately after birth with severe hypotonia. Two of them needed artificial ventilation because of respiratory insufficiency. All three pregnancies had been complicated by reduced fetal movements and moderate cerebral ventricular dilatation and in two of the three there was also polyhydramnios and congenital talipes. In all three infants congenital myotonic dystrophy was suspected after diagnosing myotonia in the mother. This was done by observing that none of the mothers were unable to release their grip immediately on command after shaking hands. Ophthalmological examination of the women revealed polychromatic lens crystals characteristic of myotonic dystrophy. Congenital myotonic dystrophy was confirmed by DNA analysis, as well as myotonic dystrophy in the mothers. All had an expansion of the number of cytosine-thymine-guanine(CTG)-trinucleotides in a part of the myotonic dystrophy protein-kinase gene. The first two infants died after 2 days and 15 months respectively.

Spinocerebellar ataxia type 7 (SCA7): first report of a systematic neuropathological study of the brain of a patient with a very short expanded CAG-repeat.

Spinocerebellar ataxia type 7 (SCA7) represents a very rare and severe autosomal dominantly inherited cerebellar ataxia (ADCA). It belongs to the group of CAG-repeat or polyglutamine diseases with its underlying molecular genetical defect on chromosome 3p12-p21.1. Here, we performed a systematic study of the neuropathology on unconventional thick serial sections of the first available brain tissue of a genetically confirmed late-onset SCA7 patient with a very short CAG-repeat expansion. Along with myelin pallor of a variety of central nervous fiber tracts, we observed i) neurodegeneration in select areas of the cerebral cortex, and ii) widespread nerve cell loss in the cerebellum, thalamus, nuclei of the basal ganglia, and brainstem. In addition, upon immunocytochemical analysis using the anti-polyglutamine antibody 1C2, immunopositive neuronal intranuclear inclusions bodies (NI) were observed in all cerebellar regions, in all parts of the cerebral cortex, and in telencephalic and brainstem nuclei, irrespective of whether they underwent neurodegeneration. These novel findings provide explanations for a variety of clinical symptoms and paraclinical findings of both our and other SCA7 patients. Finally, our immunocytochemical analysis confirms previous studies which described the presence of NI in obviously degenerated brain and retinal regions as well as in apparently well-preserved brain regions and retina of SCA7 patients.

Von Hippel-Lindau disease: new strategies in early detection and treatment.

UNLABELLED: Von Hippel-Lindau disease is an autosomal dominant inherited disorder causing hemangioblastomas of the central nervous system (CNS), retinal hemangiomas, renal cell carcinomas, pheochromocytomas, pancreatic and liver cysts, and epididymal cystadenomas. PURPOSE: Since 1976, we have periodically screened for the lesions in a large affected family and were able to evaluate new strategies in detection and treatment. PATIENTS AND METHODS: A total of 23 individuals underwent the screening program. A multidisciplinary team of physicians was involved. RESULTS: In 13 patients (7 females and 6 males), a total of 31 tumors was detected; hemangioblastoma of the CNS (9), retinal angioma (4), renal involvement (8), pheochromocytoma (4), pancreatic lesions (4), and liver lesions (2) were diagnosed by periodic family screening. On the basis of more than 10 years of experience and current literature, new criteria for diagnosis and treatment have been proposed. CONCLUSION: The von Hippel-Lindau disease gene appears to be a tumor suppressor gene, and its absence or a defect in its structure is responsible for the predisposition to the disease. Tumor development depends on a somatic second mutation in the homologous allele. That means, in disease-gene carriers, tumor growth may begin at any age. Most of the lesions can be treated successfully when diagnosed in time. Periodic screening by a multidisciplinary team has to be continued lifelong.

Sutural cataract, retinitis pigmentosa, microcephaly and psychomotor retardation. A new autosomal recessive disorder?

We report four children (three sibs and one sporadic case) with congenital sutural cataract (opacity of the sutures of the crystalline lens), retinitis pigmentosa (leading to diminished visual acuity), microcephaly, and moderate to severe psychomotor retardation. The three sibs (two F and one M) were born to healthy, consanguineous Moroccan parents; the sporadic case is an 11-year-old Dutch girl who presented at the age of nine months with a small head circumference (third percentile) and sutural cataract. Psychomotor development was retarded in all cases, retinitis pigmentosa became evident during middle or late childhood. Congenital cataract has been described in association with a large number of various congenital abnormalities, such as renal, nervous system, skeletal, dermal and ocular (including retinal) defects. A computer-assisted literature search has not revealed similar cases to those presented here. The cases described here appear to have a previously undescribed combination of ophthalmological and cerebral abnormalities. The inheritance of the condition appears to be autosomal recessive as a brother and two sisters (offspring of normal consanguineous parents) are affected. The differential diagnosis is discussed.

Retinal dystrophy in long chain 3-hydroxy-acyl-coA dehydrogenase deficiency.

BACKGROUND: Long chain 3-hydroxyacyl-CoA-dehydrogenase (LCHAD) is one of the enzymes involved in the breakdown of fatty acids. A deficiency of this enzyme is associated with life threatening episodes of hypoketotic hypoglycaemia during prolonged fasting. Neuropathy and retinopigmentary changes were mentioned in only a few cases. METHODS: The case histories of two girls, aged 8 and 15 years, with LCHAD deficiency are reported. RESULTS: Both children with LCHAD deficiency exhibited extensive macular pigmentary depositions and a 'salt and pepper' scattering of pigment in their retinas. The patients have decreasing visual acuity. CONCLUSION: The early recognition of LCHAD deficiency can increase the life expectancy in these patients through avoiding catabolism and through appropriate diets. Patients tend to be free of symptoms between attacks, however. Testing for the disorder, therefore, should be included in the diagnostic process for children with retinal dystrophy, in particular when other clinical symptoms are known to have occurred.

Visual behaviours of neurologically impaired children with cerebral visual impairment: an ethological study.

BACKGROUND/AIMS: Visual functions of neurologically impaired children with permanent cerebral visual impairment (CVI) can be difficult to determine. This study investigated the behavioural profile of CVI children by means of ethological observations in order to gain a better understanding of their visual functions. METHODS: Video registrations of nine subjects who were unable to undergo more orthodox methods of visual function testing were observed and analysed by an ethologist. RESULTS: A series of behaviours (direct signs) and supportive or confirming behavioural elements (indirect signs) indicating some visual perception in the children were found. CONCLUSION: Detailed ethological observations of visual behaviour were shown to be useful for analysing visual functions of children with permanent CVI.

Genetic heterogeneity of hereditary motor and sensory neuropathy type VI.

Charcot-Marie-Tooth disease comprises a heterogeneous group of neurologic disorders that shape peripheral motor and sensory neuropathy. A classification of these disorders was proposed in 1975, defining seven types of hereditary motor and sensory neuropathy. Clinical features of hereditary motor and sensory neuropathy type VI are muscle weakness and atrophy in leg and hand muscles, leading to progressive disability and loss of vision and progressing to blindness due to optic atrophy. Hereditary motor and sensory neuropathy type VI was first reported in 1879 by Vizioli, who described a kinship in which a father and two sons presented with peroneal muscular atrophy in association with optic atrophy. Since then, at least nine similar cases have been reported: three sporadic cases, two pairs of siblings who were offspring of consanguineous parents, and one pair of siblings who were offspring of unrelated parents suggesting autosomal recessive inheritance. Vertical transmission has been reported only by Vizioli. We present a father and two offspring (one boy and one girl) with the above-mentioned characteristic features of hereditary motor and sensory neuropathy type VI. Vizioli's kinship and either an autosomal recessive or autosomal dominant pattern of inheritance.

Blepharophimosis, ptosis, polythelia and brachydactyly (BPPB): a new autosomal dominant syndrome?

A father and two sons with blepharophimosis, ptosis, polythelia and brachydactyly are presented, apparently without other abnormalities. The features do not fit into any previously described syndrome. This condition may represent a hitherto undescribed syndrome, although resemblance with the blepharophimosis-ptosis-epicanthus inversus syndrome exists. Inheritance is probably autosomal dominant.

Cleft lip and cone-rod dystrophy in a consanguineous sibship.

Three siblings from a consanguineous marriage were found to have a cleft lip. Two of them developed a progressive retinopathy which was identified as a cone-rod dystrophy. It is suggested that this association may represent a hitherto unreported entity with an autosomal recessive pattern of inheritance, although chance co-occurrence cannot be excluded.

Split hand/split foot, iris/choroid coloboma, hypospadias and subfertility: a new developmental malformation syndrome?

This paper presents a patient with the following malformations: split hand and split foot on the left side, a hypoplastic fifth ray of the right hand and a hypoplastic first ray of the right foot with a small cleft between the first and second ray; eye abnormalities which consist of a complete iris coloboma of the left eye in an atypical position (cranio-temporal) and a coloboma of the choroid in the right eye; a glandular hypospadias and terato-zoospermia. Since split hand/split foot can be caused by mutations in the p63 gene, mutation analysis of this gene was performed. However, sequencing analysis did not reveal a mutation. This malformation complex may represent a new syndrome.

The Peters'-Plus syndrome: description of 16 patients and review of the literature.

Peters'-Plus syndrome is characterized by Peters' anomaly, a typical face, cleft lip and palate, short limb dwarfism, and developmental retardation. We report the follow-up of six patients in the original report, 10 yet unreported patients, and review 26 patients that have been reported in the literature. The spectrum of the syndrome is broadened by data from affected sibs which indicate that a wider range of anterior chamber cleavage disorders may be present, a cleft lip or palate need not be present, and developmental retardation may be mild or even absent. An increased foetal loss in families with Peters'-Plus syndrome may indicate intrauterine death of some foetuses affected by the syndrome. The pattern of inheritance is autosomal recessive.

Screening for retinopathy of prematurity: do former guidelines still apply?

Early detection of retinopathy of prematurity (ROP) in premature and very-low-birth-weight infants is crucial. In this retrospective study, 581 infants either with a birth weight below 1500 g or a gestational age of less than 32 weeks, or who did not fit these criteria but were judged to be at increased risk, were screened for ROP. ROP developed in 159 (27.4%). The incidence of ROP appeared to be inversely proportional to birth weight and gestational age. Infants with a birth weight below 750 g had a significantly higher risk of developing stage 3 and 4 ROP. The mean age at detection was 7.6 +/- 1.6 weeks. Nearly all of the ROP cases and all of the stage 3 and 4 cases were detected between the 5th and 10th week. Because screening should be focused on these vision-threatening stages, ophthalmic examinations should be concentrated in, but not limited to, the period between the 5th and the 10th postnatal week.

[Lacrimal duct probing in young children with a congenital lacrimal duct obstruction at the Utrecht University Medical Center: generally an effective treatment]. / Traanwegsondage bij jonge kinderen met een aangeboren traanwegobstructie in het Universitair Medisch Centrum Utrecht: doorgaans een effectieve behandeling.

OBJECTIVE: To assess the results of lacrimal duct probing in young children with epiphora, due to a congenital nasolacrimal duct obstruction. DESIGN: Retrospective, descriptive. METHOD: Data were collected from medical dossiers on the results of lacrimal duct probing in children (0-48 months) with epiphora that was done in the period from January 1, 1997 to December 31, 2001 at the University Medical Centre in Utrecht, the Netherlands. The percentage of eyes that showed complete resolution of symptoms three months after the final probing was calculated. RESULTS: Of the 89 children who had undergone lacrimal duct probing, seven were excluded and in three children (six eyes) the data could not be retrieved. In 96 of the remaining 116 eyes (83%), the symptoms disappeared: this included 96% of the age group 0-12 months (n = 25), 85% of the 13-24 months-olds (n = 55), 77% of the 25-36 months-olds (n = 22) and 57% of the 37-48 months-olds (n = 14). No complications of probing were seen. CONCLUSION: In most children in the various age groups, epiphora disappeared. Thus, children do not need to be probed in the first year of life out of fear of failure at an older age. Whether or not probing shortens the duration of epiphora cannot be determined on the basis of either this study or the literature.

A randomised comparison of bilateral recession versus unilateral recession-resection as surgery for infantile esotropia.

OBJECTIVE: Infantile esotropia, a common form of strabismus, is treated either by bilateral recession (BR) or by unilateral recession-resection (RR). Differences in degree of alignment achieved by these two procedures have not previously been examined in a randomised controlled trial. DESIGN: Controlled, randomised multicentre trial. SETTING: 12 university clinics. PARTICIPANTS AND INTERVENTION: 124 patients were randomly assigned to either BR or RR. Standardised protocol prescribed that the total relocation of the muscles, in millimetres, was calculated by dividing the preoperative latent angle of strabismus at distance, in degrees, by 1.6. MAIN OUTCOME MEASURE: Alignment assessed as the variation of the postoperative angle of strabismus during alternating cover. RESULTS: The mean preoperative latent angle of strabismus at distance fixation was +17.2 degrees (SD 4.4) for BR and +17.5 degrees (4.0) for RR. The mean postoperative angle of strabismus at distance was +2.3 degrees (5.1) for BR and +2.9 degrees (3.5) for RR (p = 0.46 for reduction in the angle and p = 0.22 for the within-group variation). The mean reduction in the angle of strabismus was 1.41 degrees (0.45) per millimetre of muscle relocation for RR and 1.47 (0.50) for BR (p = 0.50 for reduction in the angle). Alignment was associated with postoperative binocular vision (p = 0.001) in both groups. CONCLUSIONS: No statistically significant difference was found between BR and RR as surgery for infantile esotropia.

Retinitis pigmentosa in mevalonate kinase deficiency.

Retinitis pigmentosa can occur as a complication of mevalonate kinase deficiency. This may be due to the unique isoprenoid metabolism in the retina. Early detection requires awareness on the part of the treating physician.

Role of visual dysfunction in postural control in children with cerebral palsy.

INTRODUCTION: Deficient postural control is one of the key problems in cerebral palsy (CP). Little, however, is known about the specific nature of postural problems of children with CP, nor of the relation between abnormal posture and dysfunction of the visual system. AIM OF THE STUDY: To provide additional information on the association of abnormalities in postural control and visual dysfunction of the anterior or posterior part of the visual system. METHODS: Data resulting from ophthalmologic, orthoptic, neurological, neuro-radiological, and ethological investigations of more than 313 neurologically impaired children were retrospectively analyzed. RESULTS: Abnormal postural control related to ocular and ocular motor disorders consisted of anomalous head control and subsequent abnormal head posture and torticollis. The abnormal postural control related to retrochiasmatical damage of the visual system consisted of a torticollis combined with adjustment of the upper part of the body, as if at the same time adapting to a combination of defects and optimizing residual visual functions. CONCLUSION: Visual dysfunctions play a distinct role in the postural control of children with CP.

The dystrophy described by Reis and Bücklers. Separate entity or variant of the granular dystrophy?

The dystrophy originally described by Reis and Bücklers shows electron-microscopically 'rod-shaped bodies' in the region of Bowman's membrane that cannot be distinguished from the 'rod-shaped bodies' in the granular dystrophy. Some authors conclude from this finding that the dystrophy is a superficial variant of the granular dystrophy. Our findings indeed point to the fact that the keratocytes are the primary source of the opacities as is the case in the granular dystrophy. From the clinical, biomicroscopic and light-microscopic differences, however, it seems likely that both dystrophies will in future be shown to be due to different biochemical defects or that they are at least allelic forms of the same biochemical defect.