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Mandibulofacial dysostosis with microcephaly is a rare syndromic craniofacial condition caused by heterozygous loss-of-function mutations of the EFTUD2 gene on 17q21.31. Thus far, the described musculoskeletal findings in patients with this condition include proximally placed or duplicated thumbs, overlapping toes, and toe syndactyly. We describe a severe case of a patient with a 17q21.31 microdeletion and many of the phenotypic features described in mandibulofacial dysostosis with microcephaly who had bilateral proximal radioulnar synostosis and brain abnormalities. This provides further evidence of the clinical overlap among mandibulofacial and acrofacial dysostoses syndromes and expands the phenotype of EFTUD2 haploinsufficiency due to larger deletions.

Purpose: Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid α-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder. Methods: The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II. rhGAA used in this study was purified from genetically engineered Chinese hamster ovary (CHO) cells overproducing GAA. Adverse effects and efficacy of rhGAA upon cardiac, pulmonary, neurologic, and motor functions were evaluated during 1 year of the trial period. The primary end point assessed was heart failure–free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age. Results: The results of more than 250 infusions showed that rhGAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants have well passed the critical age of 1 year (currently 16, 18, and 22 months old) and continue to have normal cardiac function. Improvements of skeletal muscle functions were also noted; one patient showed marked improvement and currently has normal muscle tone and strength as well as normal neurologic and Denver developmental evaluations. Muscle biopsies confirmed that dramatic reductions in glycogen accumulation had occurred after rhGAA treatment in this patient. Conclusions: This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.

We present a single case of a young man with multiple congenital anomalies. For years, a unifying diagnosis could not be made. As his case developed, more clues came to light, but still no recognizable pattern could be identified. Ultimately, the combination of orofacial clefting, neurosensory hearing loss, choroideremia, and cognitive delays were shown to be due to an Xq21 [corrected] micro-deletion as seen on comparative genomic hybridizations studies. A review of the genes contained in this region clearly explain his constellation of findings.

Nevus of Ota is a benign congenital melanocytic lesion found most commonly in people of Asian ancestry. It is associated with an increased risk of glaucoma and uveal melanomas. Most cases are sporadic and unilateral. We present the first reported case of a brother and sister with familial, bilateral nevus of Ota.

Congenital hyperinsulinism (CHI) is a rare metabolic disease characterized by inappropriate insulin secretion in the presence of hypoglycemia. We describe the clinical presentation and management of congenital hyperinsulinism and persistent hypoglycemia in two infants. Both patients had an initial clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) but normal methylation analysis for LIT1 and H19 status. Both patients were eventually found to have mosaic uniparental disomy 11p diagnosed by single nucleotide polymorphism (SNP) array in DNA isolated from lymphoblasts and fibroblasts, respectively. We report that patients with mosaic BWS are at increased risk for both transient and refractory hypoglycemia that may need aggressive management with diazoxide, octreotide, high glucose infusion rates, and a frequent feeding regime. Our patient experience supports the case for pursuing further testing in patients with features of BWS with normal methylation studies, karyotype, and SNP arrays on blood. The next logical step is SNP array on skin biopsy to rule out mosaicism.

Advances in technology and telecommunications have opened the door for primary care pediatricians to provide a range of medical services that extend the walls of their medical home. Constraints of time, distance, and access can be overcome with electronic transmission of medical information that provide patients care when and where they need it by providers they know and trust. No longer are on-call pediatricians staying home tied to their land-line telephone, assessing acute conditions based only on parent descriptions and documenting the conversation on paper call slips. If this sounds like you, please read this article for a 2009 alternative.

Attention to a careful diagnostic work-up should be given to patients with postaxial polydactyly or apparently isolated hypothalamic hamartomas. Early recognition of the condition is critical for management, particularly for anticipating and preventing endocrine emergencies. Conservative management of the hypothalamic hamartoma should be stressed. Finally, detailed genetic counseling should be provided to the family regarding autosomal-dominant inheritance as well as the wide range of interfamilial and intrafamilial variability.

The recent progress in matrix metalloproteinases (MMPs) research has opened up many cellular targets in a variety of diseases. We have discussed some of the interesting and newly described roles of MMPs in modulating metastatic phenotype in malignancies. This information suggests a more specific and exclusive role of MMPs as important regulators of tumor cell invasion and metastasis. A great deal of room exists for redefining our current understanding of the MMPs system; the more we understand about how MMPs act, the better we will understand the pathobiology of metastasis. Research in the regulation of MMPs and the potential use of MMPs for therapeutic interventions in metastasis continues to expand. The future of therapy involving inhibitors of MMPs as a part of the armamentarium against human neoplasm should be viewed with cautious optimism. This therapeutic approach is beginning to find a place in our understanding of metastatic tumors, but with perhaps few exceptions should still be considered experimental. This area of research now needs more biological knowledge and imagination on the part of investigators to make future achievements possible.

We report 2 cases of patients with a rare multiple anomaly condition reported as Dellman (oculocerebrocutaneous) syndrome. In this article we discuss the clinical features and genetics of this condition. Notably, both of these patients have digital abnormalities which have not been previously described in the literature.

The cause of Sotos syndrome is unknown but it usually occurs sporadically. Recent studies have shown no evidence of uniparental disomy. One set of concordant monozygotic twins has been reported. We have identified the Sotos syndrome in one of two 5-year-old male monozygotic twins. Our finding of discordance in these identical twins suggests that a postconceptual mutation, or epigenetic change and/or an environmental factor may be involved in the cause of Sotos syndrome.

This study was undertaken to ascertain the prevalence of the persistent cavum septi pellucidi in children and adults by magnetic resonance imaging (MRI) and to compare the clinical indications for neuroimaging in the two age groups as a measure of group selection bias. All scans performed at West Virginia University during 1997 were reviewed for the presence of a persistent cavum septi pellucidi. The clinical indications for the MRI study were determined in 100 consecutive adult (17 years of age or older) and 100 consecutive pediatric (younger than 17 years of age) scans. In the 203 pediatric patients the prevalence of a persistent cavum septi pellucidi was 6.9%, and in the 814 adults the prevalence was 2.1%. Mental retardation/developmental delay was the clinical indication for at least 26% of the pediatric patients but was not an indication for neuroimaging in the adult study group. The known association of persistent cavum septi pellucidi with mental retardation and in several groups of patients with conditions clinically characterized by mental dysfunction suggests that the higher prevalence in the pediatric study group may primarily be the result of the patient selection bias operating through the different clinical indications for neuroimaging in the two populations.

Usher syndrome is a group of genetic disorders consisting of congenital sensorineural hearing loss and retinitis pigmentosa of variable onset and severity depending on the genetic type. It was suggested that the psychosis of Usher syndrome might be secondary to a metabolic degeneration involving the brain more diffusely. There have been reports of focal and diffuse atrophic changes in the supratentorial brain as well as atrophy of some of the structures of the posterior fossa. We previously performed quantitative analysis of magnetic resonance imaging studies of 19 Usher syndrome patients (12 with type I and 7 with type II) looking at the cerebellum and various cerebellar components. We found atrophy of the cerebellum in both types and sparing of cerebellar vermis lobules I-V in type II Usher syndrome patients only. We now have studied another group of 19 patients (with some overlap in the patients studied from the previous report) with Usher syndrome (8 with type I, 11 with type II). We performed quantitative volumetric measurements of various brain structures compared to age- and sex-matched controls. We found a significant decrease in intracranial volume and in size of the brain and cerebellum with a trend toward an increase in the size of the subarachnoid spaces. These data suggest that the disease process in Usher syndrome involves the entire brain and is not limited to the posterior fossa or auditory and visual systems.

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

We reviewed the neuroimaging studies of 40 patients with classic Sotos syndrome. The studies consisted of CT scans only in 4 patients and one or more MRI scans in 36 patients. The diagnosis of Sotos syndrome was made using well-established clinical criteria. The neuroimaging studies of each patient were evaluated subjectively by visual inspection and the chief findings were tabulated and grouped into five categories: 1) ventricular abnormalities, 2) extracerebral fluid spaces, 3) midline abnormalities, 4) migrational abnormalities, and 5) others. The most common abnormality of the cerebral ventricles was prominence of the trigone (90%), followed by prominence of the occipital horns (75%) and ventriculomegaly (63%). The supratentorial extracerebral fluid spaces were increased for age in 70% of the patients and the fluid spaces in the posterior fossa were increased in 70% also. A variety of midline abnormalities were noted but anomalies of the corpus callosum were almost universal. Gray matter heterotopias occurred in only 3 (8%) of 36 patients. Periventricular leukomalacia, presumably the result of prenatal or perinatal difficulties and unrelated to the basic condition, was the most common of the miscellaneous other abnormalities noted. The neuroimaging findings of Sotos syndrome are distinct enough to allow differentiation of this syndrome from other mental retardation syndromes with macrocephaly.

Matrix metalloproteinases (MMPs) play an important regulatory role in tissue morphogenesis, cell differentiation, tumor invasion and metastasis. Several authors have reported a direct correlation between the production of 72 kDa (MMP-2) and 92 kDa (MMP-9) type IV collagenases/gelatinases and the metastatic potential of cancer cells. Recently, we have identified the expression of both MMP-2 and MMP-9 in primary cultures of human giant cell tumor (GCT) of bone in vitro, and in tissue extracts in vivo. Interestingly, MMP-9 is not secreted by late-passaged GCT cells. It is possible that the production of MMP-9 is regulated by certain factor(s) secreted by the multinucleated giant cells in the primary culture. In order to test this hypothesis, the effect of primary-culture-conditioned medium on the expression of MMP-9 by late-passaged mononuclear stromal cells was examined. Adding conditioned medium from the primary GCT culture to the late-passaged stromal cells induced MMP-9, as evidenced by the presence of lytic bands at Mr 92000 and 72000 on a gelatin zymogram. These enzyme activities were inhibited by EDTA, a well-known inhibitor of the MMPs. We confirmed these results by Western blotting using specific antibodies and RT-PCR for MMP-2 and MMP-9. Immunofluorescence studies with specific antibodies to MMP-9 further confirmed its expression by the passaged stromal cells cultured in the primary-culture-conditioned medium. The data indicate that MMP-2 and MMP-9 are produced by the mononuclear stromal cells when cultured in GCT primary-culture-conditioned medium. This suggests that multinucleated giant cells in primary cultures secrete a factor(s) that stimulates stromal cells to produce MMP-9, which, in turn, may contribute to the aggressive behavior of GCT.

Williams syndrome results from a microdeletion of approximately 1.5 Mb of chromosome 7q11.23. Several patients have been reported with the reciprocal microduplication in association with a variety of phenotypic features including cognitive impairment and typical facial features, though only a few have had birth defects. We report on three probands with duplications within 7q11.23 of variable sizes; two with cardiovascular involvement including aortic dilation and the other with unilateral renal and gonadal agenesis. We offer a comparison with previously reported cases of duplications of 7q11.23. In light of the present cases, we recommend undertaking echocardiographic and renal ultrasound evaluation of patients with documented 7q11.23 duplications. Further, this cytogenetic abnormality should be part of the differential diagnosis for patients with aortic dilation, as well as those with unilateral renal and gonadal agenesis.

The autism spectrum disorders are a collective of conditions that have in common impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased dramatically over the past two decades. In addition, increased attention has been paid to these conditions by both lay and professional groups. These trends have resulted in an increase in the number of referrals to clinical geneticist for the evaluation of persons with autism spectrum disorders. The primary roles of the geneticist in this process are to define etiology when possible, to provide genetic counseling, and to contribute to case management. In deciding on the appropriate evaluation for a particular patient, the geneticist will consider a host of factors: (i) ensuring an accurate diagnosis of autism before proceeding with any investigation; (ii) discussing testing options, diagnostic yields, and family investment before proceeding with an evaluation; (iii) communicating and coordinating with the patient-centered medical home (PCMH); (iv) assessing the continuously expanding and evolving list of available laboratory-testing modalities in light of the published literature; (v) recognizing the expanded phenotypes of well-described syndromic and metabolic conditions that overlap with autism spectrum disorders; and (vi) defining an individualized evaluation plan based on the unique history and clinical features of a given patient. The guidelines in this paper have been developed to assist the clinician in the consideration of these factors. It updates the original publication from 2008.Genet Med 2013:15(5):399-407.

It has been suggested that the size of the corpus callosum may have diagnostic significance in cerebral palsy, although this relationship is incompletely defined. Ninety-one patients with cerebral palsy had been studied by magnetic resonance imaging in the 5-year period from 1990 to 1994. Fifty-seven of these 91 patients had a technically appropriate midsagittal magnetic resonance image for quantitative morphometric analysis. The ratio of the area of the corpus callosum to the area of the supratentorial brain was compared to published age- and gender-specific norms. Imaging findings were correlated with clinical history and cause of cerebral palsy. The corpus callosum was of normal size in 43 patients and more than 2 standard deviations below the mean in 14 patients. The causes for cerebral palsy included hypoxic ischemic encephalopathy (32), cerebral dysgenesis (8), and porencephalic strokes (6); the etiology could not be established in 11 patients. The size of the corpus callosum was highly correlated with the cause of cerebral palsy, such that all patients with cerebral dysgenesis had hypoplasia of the corpus callosum (one-sided z test, p < 0.0001). Conversely, the callosum was of normal size in 32 of 38 patients with hypoxic ischemic encephalopathy and porencephalic strokes. The presence of a hypoplastic corpus callosum is highly associated with cerebral dysgenesis as a cause for cerebral palsy.

There are conflicting reports on the relationship between cerebellar vermal lobule hypoplasia and autism. Using quantitative magnetic resonance image analysis, we measured the cerebellar vermis in 125 normal individuals with a broad age range and 102 patients with a variety of neurogenetic abnormalities. We conclude that hypoplasia of cerebellar vermal lobules VI and VII is a nonspecific finding that even occurs in several conditions with-out autistic behavior. This suggests that it is not a specific neuroanantomical marker for autism, nor is cerebellar dysgenesis likely to be solely responsible for clinical autistic behaviors.

Correction to: European Journal of Human Genetics advance online publication 18 November 2015; doi:10.1038/ejhg.2015.242 Since the publication of the above paper the authors have realised that they had omitted an important reference published online in this journal while their own paper was undergoing the review process.

This paper reviews the changes of adolescence that affect neuroendocrine and neurophysiologic functions. Normal variability in onset and progression of pubertal stages is discussed. The effects of hypothalamic and pituitary maturation and resulting changes in circulating hormone levels at the onset of secondary sexual characteristics are reviewed. Several theories and research data regarding the causes of the onset of puberty are identified. Abnormal symptoms of pubertal development are reviewed, and suggestions made for the Cleft Palate-Craniofacial team to monitor these symptoms.

Introduction: Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders (LSDs) caused by a defect in the degradation of glycosaminoglycans (GAGs). The accumulation of GAGs in MPS patients results in extensive, severe and progressive disease. Disease modifying therapy is available for three of the MPSs and is being developed for the other types. Early initiation of treatment, before the onset of irreversible tissue damage, clearly provides a favorable disease outcome. However, early diagnosis is difficult due to the rarity of these disorders in combination with the wide variety of clinical symptoms. Newborn screening (NES) is probably the optimal approach, and several screening techniques for different MPSs have been studied. Here we describe a relatively simple and sensitive method to measure levels of dermatan and heparan sulfate derived disaccharides in dried blood spots (DBS) with HPLC-MS/MS, and show that this reliably separates MPS I, II and MPS III newborns from controls and heterozygotes. Methods: Newborn DBS of 11 MPS I, 1 MPS II, and 6 MPS III patients, with phenotypes ranging from severe to relatively attenuated, were collected and levels of dermatan and heparan sulfate derived disaccharides in these DBS were compared with levels in DBS of newborn MPS I and MPS III heterozygotes and controls. Results: The levels of dermatan and heparan sulfate derived disaccharides were clearly elevated in all newborn DBS of MPS L II and III patients when compared to controls. In contrast, DBS of MPS I and III heterozygotes showed similar disaccharide levels when compared to control DBS. Conclusions: Our study demonstrates that measurement of heparan and dermatan sulfate derived disaccharides in DBS may be suitable for NBS for MPS I, II and MPS III. We hypothesize that this same approach will also detect MPS VI, and VII patients, as heparan sulfate and/or dermatan sulfate is also the primary storage products in these disorders. (C) 2012 Elsevier Inc. All rights reserved

The role of growth hormone (GH) in regulating the transport of plasma lipoproteins has not been clearly defined, but past studies suggest that GH may influence cholesterol levels. This protocol was designed to evaluate possible changes in lipid and apolipoprotein status in GH-deficient children and children with neurosecretory dysfunction (NS) before GH therapy and at intervals after GH therapy was started. Twenty children with classic GH deficiency were evaluated, and 28% were hyperlipidemic at the onset of the study. Seven children were evaluated in the NS group, and only one (14%) showed an elevated total cholesterol (TC) greater than 200 mg/dL. The mean TC for all the GH-deficient children was elevated above the normal range, but not for the NS group. The mean apolipoprotein (apo) C-III level and its heparin-precipitated fraction (HP) were also elevated in the GH-deficient group, but only the apo C-III HP was elevated in the NS group. A standard replacement dose of recombinant methionyl GH was used; and therapy had no significant effect on TC or triglyceride (TG) levels. Apo C-III HP, a marker of hypertriglyceridemia, increased after the start of therapy, but no other lipoprotein levels changed significantly in the GH-deficient group. No changes were seen with treatment in the NS group. The longitudinal design of this study allowed demonstration of the later changes in the apolipoproteins and the presence of a distinct subset of patients with both GH deficiency and hypercholesterolemia. This study supports the role of GH in modulating lipid metabolism.

Methyl-CpG binding protein 2 gene ( MECP2) testing is indicated for patients with numerous clinical presentations, including Rett syndrome (classic and atypical), unexplained neonatal encephalopathy, Angelman syndrome, nonspecific mental retardation, autism (females), and an X-linked family history of developmental delay. Because of this complexity, a gender-specific approach for comprehensive MECP2 gene testing is described. Briefly, sequencing of exons 1 to 4 of MECP2 is recommended for patients with a Rett syndrome phenotype, unexplained neonatal encephalopathy, an Angelman syndrome phenotype (with negative 15q11-13 analysis), nonspecific mental retardation, or autism (females). Additional testing for large-scale MECP2 deletions is recommended for patients with Rett syndrome or Angelman syndrome phenotypes (with negative 15q11-13 analysis) following negative sequencing. Alternatively, testing for large-scale MECP2 duplications is recommended for males presenting with mental retardation, an X-linked family history of developmental delay, and a significant proportion of previously described clinical features (particularly a history of recurrent respiratory infections).

Fetal Alcohol spectrum disorders are extremely common. The clinical impact and societal effects are tremendous. Prevention and treatment of these disorders begins with an accurate diagnosis. All health care providers who work with children (and adults) with special health care needs should be alert to these findings. The key to early diagnosis is to always keep the diagnostic possibility in the broad differential diagnoses of growth and developmental disorders. As with most conditions, early recognition and intervention is associated with better outcomes. Once an FASD is identified in a specific patient, prompt referrals and enrollment in indicated services are necessary to get the best outcomes. In this article we review the diagnostic criteria and clues to prompt early identification of FASDs. We also discuss the therapeutic options shown to be most effective for this group of individuals.

Males with duplication of the Xq28 region, including methyl CpG-binding protein 2 (MECP2), exhibit a characteristic phenotype, including developmental delay, intellectual disability, limited or absent speech, limited or absent ambulation, and recurrent respiratory infections. We report six males with MECP2 duplications identified using array comparative genomic hybridization. The minimal sizes of these duplications range from ∼0.08 to 14.13 Mb, which, to the best of our knowledge, are respectively the smallest and largest minimal size duplications molecularly characterized to date. Adjunct metaphase fluorescence in situ hybridization analysis further classified these duplications as tandem or as products of complex chromosomal rearrangements. Specifically, one complex rearrangement was described as a der(12)t(X;12)(q28;q24.33), which is the first report of a translocation involving MECP2 on Xq and chromosome 12. The other complex rearrangement was described as a rec(X)dup(Xq)inv(X)(p22.32q28)mat. Synthesis of the dysmorphic features identified in individuals with rec(X) chromosomes, including deletions in the pseudoautosomal region 1 (PAR1) at Xp22.33/Yp11.3 and duplications of the distal Xq region including MECP2, revealed a high prevalence of undescended testes (7/8) and micropenis (3/8) in this cohort. Given that micropenis is rare in the general population, but present in 38% of individuals in this cohort, a dosage anomaly at one or both loci may be a significant risk factor for this condition. Therefore, we recommend microarray testing for patients with unexplained micropenis, particularly when accompanied by other phenotypic anomalies. © 2012 Wiley Periodicals, Inc.

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations with an approximate frequency of one in 2,500 live births and a carrier frequency of one in 25. We studied 400 individuals seen at The Nebraska Regional Cystic Fibrosis Center that included 139 CF patients, 206 parents, and 55 unaffected siblings to determine the frequency of the delta F508, R117H, G542X, S549R/N, G551D, R553X, R560T, and W1282X mutations. In addition, we determined haplotypes on each of these individual's chromosomes using four markers that included XV-2c, KM-19, pMP6d.9, and G2. Results from this study showed that the delta F508 mutation was present in 70% of CF chromosomes. Of the 139 CF patients 74 (53%) were homozygous for the delta F508 deletion, 47 (34%) were heterozygous for the delta F508 deletion and an unknown mutation, and 18 (13%) carried two unknown mutations. Four additional mutations were also found in our population and included G542X (6%), G551D (5%), R553X (4%), and R560T (1%). One patient was documented to be a compound heterozygote for G542X/G551D. A polymorphism, F508C, that has previously been reported in several families was also present in our study. The most common haplotype associated with the delta F508 deletion in our CF patients was the E haplotype (CF Consortium B) while other mutations were associated with a variety of haplotypes.

The development and refinement of array comparative genomic hybridization has led to expanded applications as a diagnostic tool. Recent reports suggest a high diagnostic yield for array comparative genomic hybridization in autism spectrum disorders. The objective of this study was to determine the diagnostic yield in array comparative genomic hybridization for autism at the University of Nebraska Medical Center. The authors report the diagnostic yield of array comparative genomic hybridization in 89 samples with a primary indication of autism. Clinical information was reviewed for 89 identified cases. Twenty-one cases were excluded because of ambiguous information regarding the diagnosis, a diagnosis other than autism, or abnormal karyotype. Of 68 cases referred for array comparative genomic hybridization testing with a primary indication of autism, 14 (21%) had abnormal findings. This study supports array comparative genomic hybridization in the etiologic evaluation of autism and elevation of array to a first tier diagnostic test.

The recent progress in matrix metalloproteinases (MMPs) research has opened up many cellular targets in a variety of diseases. We have discussed some of the interesting and newly described roles of MMPs in modulating metastatic phenotype in malignancies. This information suggests a more specific and exclusive role of MMPs as important regulators of tumor cell invasion and metastasis. A great deal of room exists for redefining our current understanding of the MMPs system; the more we understand about how MMPs act, the better we will understand the pathobiology of metastasis. Research in the regulation of MMPs and the potential use of MMPs for therapeutic interventions in metastasis continues to expand. The future of therapy involving inhibitors of MMPs as a part of the armamentarium against human neoplasm should be viewed with cautious optimism. This therapeutic approach is beginning to find a place in our understanding of metastatic tumors, but with perhaps few exceptions should still be considered experimental. This area of research now needs more biological knowledge and imagination on the part of investigators to make future achievements possible.

The case of a young man with multiple brain and somatic anomalies that presented diagnostic difficulties, is discussed in this report. A majority of his features were suggestive of Joubert syndrome--although it was felt that he did not fully meet diagnostic criteria. The subsequent evaluations included a magnetic resonance image of the brain, that was found to be consistent with pontine tegmental cap dysplasia. Chromosomal microarray studies showed a 2q13 deletion. A gene associated with Joubert syndrome, NPHP1, is within this region. This case highlights several important aspects of the diagnosis and nosology of malformations of the mid-hind brain.

Pili (P) and opacity-associated proteins (Opa) facilitate Neisseria gonorrhoeae attachment to human fallopian tube epithelium. Subsequent effects on invasion are unproven. Computerized image analysis was used to study the effects of attachment factors on invasion by comparing a P+Opa+ variant to a P-Opa- variant of strain R10 in the fallopian tube organ culture model. Gonococci in sections of infected fallopian tube tissue were identified with FITC-labelled monoclonal anti-gonococcal antibodies. Nomarski DIC microscopy was used to establish anatomic boundaries that excluded extracellular gonococci from invasion measurements. The area of intracellular fluorescence served as an index of gonococcal invasion. With conservative criteria to exclude extracellular gonococci, the per cent of the intracellular area occupied by fluorescent P+Opa+ gonococci was 18% compared to 4.7% for the P-Opa- variant (P0.001). Data suggest that P+Opa+ organisms invaded deeper than P-Opa- microbes over the same time period (P = 0.029). Intra-observer variation in invasion measurements was not significant (Por = 0.85), and inter-observer correlation was high (correlation coefficient = 0.96). Computerized image analysis is a rapid, reliable means of quantifying gonococcal invasion of fallopian tube epithelium. We conclude that gonococcal attachment factors can facilitate events which enhance gonococcal invasion of fallopian tube epithelium.

A review of the advances in diagnostic techniques for evaluation of children with idiopathic mental retardation is presented. The current status of the use of clinical genetics, cytogenetics, molecular genetics, and neuroimaging in evaluating children with mental retardation is emphasized. Special attention is given to the evaluation of children with mental retardation and "autism" or "cerebral palsy."

Purpose: To determine adherence to the American Academy of Pediatrics guidelines for thyroid screening in children with Down syndrome among primary care providers in the states of Oklahoma and Nebraska. Methods: We sought to identify all children with Down syndrome born in Oklahoma and Nebraska between 1994 and 2004 and review their medical records for evidence of thyroid screening. Patients were identified through a State Department of Health birth defects registry in Oklahoma and through participation in genetics clinics and laboratories in Nebraska and Oklahoma. Charts obtained from primary care providers were reviewed and the number of actual thyroid screens was compared with the number of recommended screens for each individual during the study period. Results: In Oklahoma, 13% of participating children received all thyroid screens recommended in the guidelines. In Nebraska, 14% of children received all recommended thyroid screenings. Among participants in Oklahoma, a mean of 34% of recommended thyroid screenings were performed. In Nebraska, a mean of 45% of recommended thyroid screenings were performed. Conclusions: The level of adherence to the American Academy of Pediatrics guidelines for thyroid screening in children with Down syndrome is low. Factors contributing to this low level of adherence need to be identified and addressed.

Orofacial clefts are frequently associated with other congenital malformations. Studies vary in incidence and types of anomalies. Objective: To evaluate associated malformations in orofacial cleft patients at a major research hospital. Study Design: Medical records of 1127 patients, in the Cleft Palate / Craniofacial Clinic, Boys Town National Research Hospital, from January 1980 through February 2000 were reviewed. Patients were divided into two categories: 1) cleft palate only (CP), and 2) cleft lip, with or without cleft palate (CL±P). Further categorization included location and type, if any, of other congenital malformations.Results: 47.2% of patients had CP and 52.8% had CL±P. 32.2% of all cleft patients had associated congenital malformations. The orofacial region was the most common site, followed by cardiovascular, central nervous, and skeletal systems. Congenital malformations were more common in CP (38.7%), than CL±P(26.4%). Of malformations diagnosed, 63.1% were chromosomal/syndromic anomalies while 36.9% were non-chromosomal/syndromic. Conclusions: Recognition of the spectrum of congenital malformations,associated with orofacial clefting, is essential for further diagnostic testing and in some cases genetic counseling.

The autism spectrum disorders represent a collective of neurogenetic conditions that have in common altered socialization and communication. Much attention has been given lately to the marked increased in the reported incidence of these conditions. Significant debate also exists as to the basis of the reported increase. Regardless, clinical geneticists and pediatric neurologists alike are seeing a tremendous increase in the number of referrals for autism and related conditions. Continuing advances in genetic testing provide a moving target for the clinician in determining an appropriate diagnostic plan. In this article, we review the most recent advances in genetic testing technology and their potential application to the etiologic evaluation of patients with autism spectrum disorders.

A wide cavum septum pellucidum defined as a separation of greater than 1 cm of the leaves occurs uncommonly. Nine children with wide cavum septum pellucidum were studied; 8 were abnormal. Observed abnormalities included cognitive impairment (8), seizures (4), hypoplasia of the corpus callosum (4), optic nerve hypoplasia (2), and growth failure (4). The incidence of intellectual dysfunction, the association with midline anomalies of the brain, and growth failure all suggest that wide cavum septum pellucidum may represent part of a spectrum of midline brain anomalies.

Newborn screening fact sheets were last revised in 1996 by the Committee on Genetics of the American Academy of Pediatrics. These fact sheets have been revised again because of advances in the field, including technologic innovations such as tandem mass spectrometry, as well as greater appreciation of ethical issues such as informed consent. The fact sheets provide information to assist pediatricians and other professionals who care for children in performing their essential role within the newborn screening public health system. The newborn screening system consists of 5 parts: (1) newborn testing; (2) follow-up of abnormal screening results to facilitate timely diagnostic testing and management; (3) diagnostic testing; (4) disease management, which requires coordination with the medical home and genetic counseling; and (5) continuous evaluation and improvement of the newborn screening system. The following disorders are reviewed in the newborn screening fact sheets (which are available at www.pediatrics.org/cgi/content/full/118/3/e934): biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia, homocystinuria, maple syrup urine disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, phenylketonuria, sickle cell disease and other hemoglobinopathies, and tyrosinemia.

The purpose of this research study was to evaluate the communication of individuals with Sotos syndrome in order to better characterize common speech and language patterns. Sixteen children with Sotos syndrome received an in-depth communication assessment using standardized procedures. Assessments of speech skills, language skills, voice, fluency, and social-pragmatic interactions were completed. Results of the evaluations indicated that individuals with Sotos syndrome are prone to: (a) language impairments (particularly expressive), (b) speech sound production impairments, (c) voice impairments, (d) dysfluencies (stuttering), and (e) average social-behavioral pragmatic interaction characteristics.

We present an 11-month-old girl with congenital ocular motor apraxia (COMA) and Joubert syndrome found to have a compound heterozygous mutation in the NPHP1 gene that is responsible for juvenile nephronophthisis type 1. The association of congenital ocular motor apraxia and juvenile nephronophthisis is reviewed. The patient does not currently manifest signs of renal failure, although her mutation indicates that she is at risk for the development of juvenile nephronophthisis type 1.

The records of all patients attending a neurosensory genetics clinic over an 11-year period were reviewed. Of the 450 patients seen, 31 presented with sensorineural hearing loss, hypotonia, and delay in the acquisition of motor milestones. Of these, 4 children were found who did not have an etiologic diagnosis such as Down syndrome or cerebral palsy. Vestibular testing revealed hypoactive labyrinthine function in all 4 of the cases, and careful imaging of the temporal bone showed anomalous development of the cochlea, vestibule, and semicircular canals in 3 of the 4 cases. None of the patients had ataxia, tremor, or significant nystagmus. Over time, the hypotonia improved in all, and none were felt to have cognitive deficits. These cases demonstrate that hypoactive labyrinthine function may be associated with hypotonia that is severe enough to result in delayed acquisition of motor milestones. The patients followed the typical remitting course of “benign congenital hypotonia.” The distinguishing clinical feature is the presence of moderate to profound sensorineural hearing loss in all of the patients. ( J Child Neurol 2003;18:171—173).

Giant cell tumor (GCT) of bone is a progressive, potentially malignant process that destroys skeletal tissue. It consists of multinucleated giant cells, which are hypothesized to be derived from a monocyte/macrophage lineage and mononuclear stromal cells, and the precise relationship of these cells is not fully understood. Recently, we demonstrated that the production of matrix metalloproteinase-9 (MMP-9) in GCT stromal cells is regulated by certain factor(s) secreted by the multinucleated giant cells. In the present study, we evaluated for the presence of interleukin-1beta (IL-1beta) and attempted to establish its possible role for the induction of MMP-9 in GCT stromal cells. Using enzyme-linked immunosorbent assay (ELISA), we have demonstrated that the primary GCT cultures secrete both IL-1beta and MMP-9. The addition of monoclonal antibody (mAb) against IL-1beta partially abrogated, but did not abolish, MMP-9 expression. Our results on gelatin zymography, reverse transcriptase-polymerase chain reaction (RT-PCR), and immunofluorescence showed that GCT stromal cells did not express MMP-9, although treatment with IL-1beta induced MMP-9 expression in a dose-dependent manner, and the secretion peaked 24 h after stimulation and then plateaued. Studies with cycloheximide, a protein synthesis inhibitor, demonstrated that de novo protein synthesis is required for IL-1beta induced MMP-9 expression. Moreover, nuclear run-on analysis has revealed that IL-1beta significantly increased MMP-9 gene transcription in GCT stromal cells. The data suggest that IL-1beta secreted by the multinucleated giant cells in GCT may be one of the factors responsible for the induction of MMP-9 at the transcriptional level in GCT stromal cells in vivo. We conclude that GCT has a self-stimulatory system for the production of MMP-9, and the ability of stromal cells to produce MMP-9 with appropriate stimuli, such as IL-1beta, and possibly in concert with other cytokines may contribute to the aggressive and potentially malignant behavior of GCT.

Ocular albinism is distinguished from the more common oculocutaneous albinism by the presence of normal pigmentation of skin and hair in the former condition. Recent studies of ocular albinism have shown that the hypopigmentation of the optic fundus is associated with a number of anomalies of neuronal wiring involving the visual system. We present a patient with ocular albinism who also has a hypoplastic corpus callosum as determined by analysis of midsagittal magnetic resonance imaging scans. Previous studies of the hypoplastic corpus callosum indicate that this anomaly is a defect in neuronal migration as well. The finding of a hypoplastic corpus callosum in a patient with ocular albinism suggests a more generalized defect in neuronal migration not limited to the visual system. ( J Child Neurol 1990;5:341-343).

The purpose of the medical genetic evaluation is to identify the etiology of the hearing loss. To do so requires a multidisciplinary team that includes the otolaryngologist, audiologist, medical geneticist, and radiologist. A number of tests and procedures are now available to assist in the search for the cause of hearing losses. The importance of sensitivity when providing genetic counseling is emphasized. Molecular genetics offers potential for continued progress in understanding the etiologies of hearing loss. Recent advances in this area are discussed.