Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.

The genetic aetiology of autism remains elusive. Occasionally, individuals with Cowden syndrome (a cancer syndrome) and other related hamartoma disorders such as Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like conditions, are characterised by germline PTEN mutations, and may have neurobehavioural features resembling autism as well as overgrowth and macrocephaly. Therefore, we undertook PTEN gene mutation analysis in 18 subjects mainly prospectively ascertained with autism spectrum disorder and macrocephaly. Of these 18 autistic subjects (13 males and five females; ages 3.1-18.4 years) with a head circumference range from 2.5 to 8.0 standard deviations above the mean, three males (17%) carried germline PTEN mutations. These three probands had previously undescribed PTEN mutations: H93R (exon 4), D252G (exon 7), and F241S (exon 7). They had the larger head circumference measurements amongst all our study subjects. The three residues altered in our patients were highly evolutionarily conserved. We suggest that PTEN gene testing be considered for patients with autistic behaviour and extreme macrocephaly. The gene findings may impact on recurrence risks as well as medical management for the patient.

Association between pupillary light reflex and sensory behaviors in children with autism spectrum disorders.

Atypical pupillary light reflexes (PLR) has been observed in children with autism spectrum disorders (ASD), which suggests potential autonomic nervous system (ANS) dysfunction in ASD. ANS is also involved in modulating sensory processing and sensory dysfunction has been widely reported in children with ASD. However, the potential association between physiological measurements of PLR and behavioral observations (e.g. sensory behaviors) has not been examined extensively in literature. In this study, we investigated the potential correlation between PLR and frequently observed sensory behaviors in children with ASD. We found a significant association between PLR constriction amplitude and a set of sensory behaviors in the ASD group but not in typically developing children. Children with ASD who showed more atypical sensory behaviors also had smaller PLR constriction amplitudes. A smaller PLR constriction amplitude suggests lower parasympathetic modulation. This observation implies that some atypical sensory behaviors in children with ASD could be associated with decreased parasympathetic modulation.

Unique X-linked mental retardation syndrome with fingertip arches and contractures linked to Xq21.31.

We studied 10 members of a 4 generation Missouri kindred with a dominant mental retardation syndrome with increasing severity in males. The 21 year-old propositus presented with severe mental retardation, microcephaly, asymmetric face, exotropia, hypogonadism, joint hypermobility, rocker bottom feet, and 10 low digital arches. Two brothers and a male cousin had similar features. The mother, sister, niece, maternal aunt, female cousin, and grandmother were examined and each had 8 to 10 low digital arches. Five of the women had exotropia and one had pes cavus feet. Chromosome analysis for fragile X in multiple relatives was normal. To determine the likelihood that this was an X-linked syndrome. DNA from relatives was hybridized to probes which detect 13 different loci spanning the X-chromosome. A peak LOD score of 2.78 at theta equal to 0.0 was calculated for the syndrome locus and DXYS1 (pDP34). The more distal Xq loci showed increasing recombination with the syndrome locus. These results are consistent with location for this syndrome near Xq21.31, the chromosomal locus for DXYSI.

Value of a clinical morphology examination in autism.

In an effort to delineate more homogeneous autism subgroups for genetic study, we evaluated 133 consecutive individuals referred to the University of Missouri Autism Center. Each index case underwent a diagnostic evaluation, including a clinical morphology examination, laboratory studies, brain MRI, EEG, and collection of historical, medical, and family data. The 71% (94/133) who fulfilled DSM-IV and CARS autism diagnostic criteria were included in this study. Six of 94 were diagnosed with a known genetic disorder. Of the remaining 88 with apparently "idiopathic autism," 58% (51/88) were phenotypically normal, 22% (19/88) were clearly abnormal, and for 20% (18/88) the clinical morphology examination was equivocal. The percentage of phenotypically abnormal individuals is higher than generally thought and disagrees with the perception that children with autism are usually normally formed. The phenotypically abnormal individuals were 10 times more likely to be diagnosed with a known genetic syndrome (21% vs. 2%) and were more than twice as likely (29% vs. 14%) to have structurally abnormal brain MRIs than the phenotypically normal propositi. Moreover, the male to female ratio correlated with the presence of physical anomalies. The total study group had a male to female ratio of 4.2:1; the morphologically normal subgroup, defined on the basis of a normal physical examination, had a sex ratio of 7.5:1 and the normal subgroup, defined on the basis of both a normal physical examination and a structurally normal brain by MRI had a 23:1 sex ratio. For the phenotypically abnormal subgroup, the sex ratio was 1.7:1. Since differences in sex ratio are presumably a reflection of differences in genetic constitution, we postulate that the phenotypically normal subgroup of individuals with "idiopathic autism" is genetically different from the phenotypically abnormal individuals and that differences in the sex ratio in different autism populations is one indicator of a population's genetic heterogeneity.

Head circumference is an independent clinical finding associated with autism.

Occipitofrontal circumference (OFC) is one of the few physical findings in autism that varies significantly from the norm and is distinct and measurable. As part of a study of genetic heterogeneity of autism, we scrutinized data from a large sample of patients with idiopathic autism (N = 137), using OFC as the categorizing variable. The OFC standard deviation (OFCSD) values of the autistic propositi (0.61+/-1.6) varied significantly from that of the normal population (0.0+/-1.0), (P<0.001). Comparison of the macrocephalic (OFCSD > 2.0, N = 32) with the normocephalic individuals (-2 SD < OFCSD < +2 SD, N = 95) showed no significant differences in sex ratio, morphological status, IQ, seizure prevalence, or recurrence risks. The macrocephalic individuals were slightly less apt than those with normocephaly to have a family history of Attention Deficit Hyperactivity Disorder (ADHD) (P<0.05). Each clinical subgroup of autism propositi, defined on the basis of phenotypic status, type of onset, seizure history, or IQ, had a higher than normal mean OFC indicating that macrocephaly is an independent clinical trait in autism. As in the non-autistic population, macrocephaly was highly familial with 45% of the macrocephalic and 37% of the normocephalic propositi having at least one macrocephalic parent. Microcephaly, however, was an independent significant variable that predicted the presence of other phenotypic or genetic traits and outcome. The microcephalic patients were more likely to have abnormal physical morphology, structural brain malformations, lower IQ, and seizures. Their sex ratio was closer to normal, and their relatives had a higher incidence of seizures.

Macrocephaly with hamartomas: Bannayan-Zonana syndrome.

Familial macrocephaly with mesodermal hamartomas is described as a distinct syndrome in nine individuals from four families. Constant manifestations include symmetrical macrocephaly without ventricular enlargement, mild neurological dysfunction, and postnatal growth deceleration. Speech and motor delays observed in all the children were usually well compensated by adulthood. Two children had mild mental retardation and seizures which may have been related to intracerebral hemorrhage in one. Mesodermal hamartomas were present in affected persons from all four families, with 60% of individuals manifesting only discrete lipomas and hemangiomas. More serious tumors, including intracerebral hemangiomas, hemangiomatous involvement of the bone, and aggressive lipomas occurred in 40%. Other findings that make it possible to delineate a recognizable syndrome include down-slanting palpebral fissures (66%), a high palate (67%), joint hyperextensibility (55%), pectus excavatum (22%), strabismus or amblyopia (33%), and prolonged drooling (44%). The Bannayan-Zonana syndrome is an autosomal-dominant trait with male predominance of affected individuals.

The use of the Foster & Freeman Fx5 Fibre Finder in forensic textile examinations.

The Fx5 Fibre Finder has been developed by Foster & Freeman Ltd to automatically search tape lifts for coloured fibres specified by the operator. Experiments and casework studies have been conducted to assess primarily the performance of the instrument but also, where possible, to compare it with manual searching. Tape lifts have always been manually searched at this laboratory and it is a laborious task. The use of a machine such as the Fx5 would release a scientist from many hours of low power microscopy to be free for other duties and therefore could be a valuable labour saving device in forensic textile examination.

Prevalence of autism in Missouri: changing trends and the effect of a comprehensive state autism project.

To assess change in autism prevalence in Missouri from 1988 until 1995, computerized client registries from the Regional Diagnostic Centers were analyzed. In the five to nine year age group, the prevalence rose thirty fold from 0.15 to 4.8 per 10,000. The study period coincides with the establishment of the Missouri Autism Project suggesting that provision of services will increase the apparent prevalence figures and that autistic disorders were previously underdiagnosed in Missouri.

Simultaneously measured pupillary light reflex and heart rate variability in healthy children.

We investigated the potential inter-relationship between two measures of autonomic nervous system: pupillary light reflex (PLR) and heart rate variability (HRV), in healthy children of 8-16 years old. PLR was measured at both dark- and light-adapted conditions with various stimulation intensities. Simultaneously measured HRV was obtained in five different PLR testing phases: before PLR test, light-adapted PLR test, dark adaptation, dark-adapted PLR test and after PLR test. The frequency domain HRV parameters measured during the PLR test were significantly different from those measured during rest. Both the regression analysis and factor analysis indicated that PLR and HRV parameters were not correlated, which suggests that they may provide complementary assessment of different aspects of the overall autonomic nervous system.

Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood. Four new cases.

Cold-induced sweating syndrome (CISS), a rare autosomal recessive disorder, is genetically heterogeneous. Deficiency of the CRLF1 and the CLCF1 gene functions results in CISS1 and CISS2, respectively. So far, only a single patient with CISS2 has been reported. Here we describe four new cases of CISS, two additional patients with CISS2 (confirming locus heterogeneity) and two patients with CISS1. Their case histories are given in detail to emphasize the striking similarity of their presentation, which makes a clinical differentiation impossible. All four cases had a uniform presentation in the neonatal period, much like Crisponi syndrome - inability to suckle and swallow due to facial and bulbar weakness; excessive startle and trismus-like facial contractions when crying or being handled; apnoeic spells; episodic unexplained fevers (up to 41 degrees C) and associated seizures or even sudden death; erythematous skin rashes; and camptodactyly. Thus it is evident that Crisponi syndrome is the pediatric manifestation of both CISS1 and CISS2. Signs abate during infancy and most children have a normal psychomotor development. During the first decade all children develop scoliosis and abnormal sweating which is the most disabling symptom in adulthood. We report that cold-induced sweating can be effectively treated. Detailed clinical observations, correlated with the findings from basic science research, may serve to elucidate the role(s) of this important cytokine complex in embryonic and postnatal development.

Joubert syndrome is not a cause of classical autism.

A previous report noted a 27% prevalence of autism in Joubert syndrome (JS), raising the question of overlapping etiologies. Family studies have shown that autism is characterized by family loading for a number of specific behavioral and psychiatric disorders and that the sib recurrence risk is around 4%. The purpose of this study is to determine whether children with Joubert and their families show behavioral or genetic characteristics similar to autism. Thirty-one volunteer Joubert families were identified. Parents completed a semi-structured family history interview and the Autism Behavioral Checklist. Rates of family loading for neuropsychiatric disorders in the JS families were compared to autism family history data and Down syndrome (DS) controls. The JS families had significantly lower rates of autism, alcoholism, cognitive, and language disorders than the autism families. Their rate of depression was lower, but not significantly different from that found in autism families. None of the JS children met the clinical cut-off for autism based on parental symptom report and the sib recurrence risk was 32% for the JS families compared to 4% for the autism and 0% for DS families. These data indicate that JS is a genetically distinct disorder from autism. Different genes with different inheritance patterns that affect neurodevelopment of the cerebellum could explain the clinical similarities previously reported in JS and autism.

Essential versus complex autism: definition of fundamental prognostic subtypes.

Heterogeneity within the autism diagnosis obscures the genetic basis of the disorder and impedes our ability to develop effective treatments. We found that by using two readily available tests, autism can be divided into two subgroups, "essential autism" and "complex autism," with different outcomes and recurrence risks. Complex autism consists of individuals in whom there is evidence of some abnormality of early morphogenesis, manifested by either significant dysmorphology or microcephaly. The remainder have "essential autism." From 1995 to 2001, 260 individuals who met DSM-IV criteria for autistic disorder were examined. Five percent (13/260) were microcephalic and 16% (41/260) had significant physical anomalies. Individually, each trait predicted a poorer outcome. Together they define the "complex autism" subgroup, comprising 20% (46/233) of the total autism population. Individuals with complex autism have lower IQs (P=0.006), more seizures (P=0.0008), more abnormal EEGs (46% vs. 30%), more brain abnormalities by MRI (28% vs. 13%). Everyone with an identifiable syndrome was in the complex group. Essential autism defines the more heritable group with higher sib recurrence (4% vs. 0%), more relatives with autism (20% vs. 9%), and higher male to female ratio (6.5:1 vs. 3.2:1). Their outcome was better with higher IQs (P=0.02) and fewer seizures (P=0.0008). They were more apt to develop autism with a regressive onset (43% vs. 23%, P=0.02). Analysis of the features predictive of poor outcome (IQ<55, functionally non-verbal) showed that microcephaly was 100% specific but only 14% sensitive; the presence of physical anomalies was 86% specific and 34% sensitive. The two tests combined yielded 87% specificity, 47% sensitivity, and an odds ratio of 4.8:1 for poor outcome. Separating essential from complex autism should be the first diagnostic step for children with autism spectrum disorders as it allows better prognostication and counseling. Definition of more homogeneous populations should increase power of research analyses.

Spontaneous arterial perforation: the Ehlers-Danlos specter.

The Ehlers-Danlos syndrome (EDs) is one of the most frequently inherited disorders of connective tissue. Type IV EDs, the arterial-ecchymotic type, is of concern to vascular surgeons because it is frequently associated with spontaneous catastrophic bleeding. This article summarizes our experience with five members of a family and reviews the 31 patients with type IV EDs described in the literature. The 22 male and 14 female patients had a mean age of 26 years. The 36 patients included 23 with easy "bruisability," 22 with hypermobility of their joints (especially the fingers), 13 with transparent skin, and 11 with excessive elasticity of the skin. The patients had 41 episodes of hemorrhage and 29 vascular surgical procedures. Twenty-nine of the patients had an aneurysm or a dissection, whereas eight patients had arteriovenous fistulas. Arteriography was associated with a complication rate of 67%. The prognosis for a patient with type IV EDs is poor; 44% die before surgery and 19% die during the operative period. Bleeding should be managed nonoperatively when possible. Fifty-one percent die before reaching 40 years of age. Arteriography should be avoided. The standard repair of aneurysms and perforations is unlikely to be successful because of marked vessel friability. Bleeding vessels should be repaired with buttressed sutures and no tension or should be ligated. Genetic counseling with assay of collagen production is recommended for family members.

Mixed hearing loss in Larsen syndrome.

A mixed bilateral hearing loss is described in a child with classical Larsen syndrome. The presence of a residual conductive loss after successful placement of ventilating tubes suggests that the conductive loss is due to an ossicular abnormality. In Larsen syndrome, characterized by multiple joint dislocations and bony malformations, the ossicular joints may also be affected.

Cytogenetics of bilateral renal cell carcinoma.

We analyzed cytogenetically 6 tumors from 4 patients with bilateral renal cell carcinoma. Comparison among findings in these patients with bilateral disease and previously reported cases of unilateral tumor demonstrates that bilaterality is associated with a more frequent loss of a sex chromosome, and gain of chromosomes 7 and 3, whereas unilateral tumors often are associated with loss of chromosome 3 material. It is proposed that bilateral tumors are distinct genetically from unilateral tumors and that most bilateral tumors have a genetic propensity to either enhanced metastatic spread to other renal tissue or spontaneous degeneration.

Clinical findings in patients with marker chromosomes identified by fluorescence in situ hybridization.

Twenty-seven patients carrying marker chromosomes were previously collected, characterized by cytogenetic techniques, and identified by stepwise fluorescence in situ hybridization (FISH) with alpha-satellite DNA probes. Clinical features of 22 patients are described here and compared to other patients with marker chromosomes similarly identified and reported in the literature.