Morphological abnormalities in children with thyroidal congenital hypothyroidism.

Several groups of investigators have reported an increased incidence of congenital anomalies in patients with congenital hypothyroidism. Furthermore, in patients with congenital hypothyroidism and mutations in genes known to be involved in thyroid development, specific extra-thyroidal abnormalities have been observed. The goal of the present study was to gain insight in the types and patterns of morphological characteristics depending on the type of congenital hypothyroidism of thyroidal origin (CH-T). In 242 Dutch CH-T patients with a thyroid agenesis, a dystopic thyroid rudiment or a eutopic thyroid gland, we performed a careful physical examination of the body surface directed to visually detectable morphological abnormalities; results were compared to a group of 1,007 Dutch control subjects. The percentage of patients with one or more major abnormalities in the total CH-T cohort (33.1%) and in patients with CH-T dystopic thyroid (37.2%) was significantly higher than in the control population (21.8%; P < 0.001). Especially in the CH-T dystopic thyroid group specific major malformations (bilateral ear pits; oligodontia) were found more frequently. Also, the percentage of patients in the total CH-T group with one or more minor anomalies (96.3%) was significantly higher than in the control group (82.5%). The careful grouping of patients according to their CH-T etiology and the types and patterns in morphological findings may be helpful in the search for novel genes involved in thyroid development.

A novel 6.14 Mb duplication of chromosome 8p21 in a patient with autism and self mutilation.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with a strong genetic etiology. Cytogenetic abnormalities have been detected in 5-10% of the patients with autism. In this study, we present the clinical, cytogenetic and array-comparative genomic hybridization (array-CGH) evaluation of a 13-year-old male with severe developmental delay, facial dysmorphic features, autism and self mutilation. The patient was found to carry a de novo duplication of chromosome region 8p21 of minimally 6.14 and maximally 6.58 Mb as ascertained by bacterial artificial chromosome (BAC)-based array-CGH. Hitherto, only a few patients with autism with cytogenetically visible duplications involving the chromosome 8p21 region have been described, but the extent of these duplications has not been determined at the molecular level. This represents the smallest rearrangement of chromosomal region 8p21 as yet found in a patient with autism. For 11 of the 36 genes with known functions located within this duplication clear transcription in the brain was found. Of those the STMN4 and DPYSL2 genes are the most likely candidate genes to be involved in neuronal development, and, if altered in gene-dosage, in the autistic phenotype of our patient.

Prevalence and patterns of morphological abnormalities in patients with childhood cancer.

CONTEXT: Constitutional gene defects predispose to cancer in children. Such tumor predisposition syndromes can be recognized by specific patterns of morphological abnormalities. OBJECTIVES: To assess the prevalence of morphological abnormalities in a large cohort of patients with childhood cancer and to identify new tumor predisposition syndromes. DESIGN, SETTING, AND PARTICIPANTS: Patients were recruited from Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands, between January 2000 and March 2003. A total of 1073 patients underwent a physical examination directed at 683 morphological abnormalities. The patient cohort consisted of 898 long-term survivors of childhood cancer and 175 newly diagnosed pediatric patients with cancer. The control group consisted of 1007 schoolchildren examined in an identical way. Mean ages of patients and controls were 21.2 and 10.4 years, respectively. MAIN OUTCOME MEASURES: Prevalence and patterns of morphological abnormalities in patients compared with controls. To prevent age bias, only age-independent abnormalities were used for overall prevalence analysis. Patients younger than 9 years were excluded from the pattern analysis. The sample was restricted to white patients to prevent ethnicity bias. RESULTS: Morphological abnormalities were significantly more prevalent in pediatric patients with cancer. Major abnormalities were present in 26.8% of patients vs 15.5% of controls (P < .001) and minor anomalies in 65.1% of patients vs 56.2% of controls (P < .001). Three or more minor anomalies were detected in 15.2% of patients vs 8.3% in controls (P < .001). Forty-two patients were diagnosed with an established tumor predisposition syndrome. Multivariate analyses showed 14 morphological abnormalities to occur significantly more often in the patient group. For 2 of these (blepharophimosis and asymmetric lower limbs), we identified statistically significant patterns of co-occurring morphological abnormalities suggestive of new tumor predisposition syndromes. Thirty-four patients fit 1 of the 2 novel tumor predisposition patterns. CONCLUSIONS: Pediatric patients with cancer show a significantly higher prevalence of morphological abnormalities compared with controls. Specific patterns of morphological abnormalities indicate possible unrecognized tumor predisposition syndromes, but validation in an independent sample is needed.

Normal values for morphological abnormalities in school children.

Clinical morphology has proven to be a strong tool in the delineation of many syndromes and a helpful instrument in molecular studies. Numerous studies have been performed investigating the prevalence of minor anomalies in various disorders; all concluding that minor anomalies can well be utilized as indicators of altered embryonic differentiation. However, for adequate evaluation, normal values for phenotypic abnormalities are essential. So far, only few studies on the frequency of phenotypic abnormalities in the normal population have been done having one thing in common: all were performed in newborn infants. We studied morphological characteristics in a group of 1,007 school children, representative for the Dutch population, through a body surface examination using detailed definitions for all morphological findings. The region of study and distribution of children over various school types was chosen in such a way that it represented the general Dutch population. The median age of the studied children was 11 years (range 8-14 years), sex ratio (M:F) was 0.93. Nine hundred twenty-three children were of Caucasian descent, 84 others of mixed ethnic backgrounds. The reliability of the examinations was tested by independent scoring of 111 children by two observers, showing a kappa score of 0.85. Normal values for the morphological findings are presented together with their age-adjusted classification. These normal values provide a valuable source for validation of classifications of phenotypic abnormalities, especially those that are depending on frequency, that is, minor anomalies and common variants. Furthermore, they will allow a proper evaluation of patterns of phenotypic abnormalities found in patient groups with specific disorders.

Cerebellar hypoplasia-endosteal sclerosis: a long term follow-up.

Cerebellar hypoplasia with endosteal sclerosis is an infrequent entity that has been described in only four cases. Major clinical symptoms are cerebellar hypoplasia causing ataxia, hypotonia, mild to moderate developmental delay, microcephaly, growth retardation, endosteal sclerosis, tooth eruption disturbances, and hip dislocations. We report on a girl with this entity, whom we followed for 11 years. The endosteal sclerosis remained stationary over time, as were the clinical neurological symptoms, but neuroadiological symptoms were slowly progressive. We provide a short review of this probably autosomal recessively inherited disorder. (c) 2005 Wiley-Liss, Inc.