PGAP2-Related Hyperphosphatasia-Mental Retardation Syndrome: Report of a Novel Patient, Toward a Broadening of Phenotypic Spectrum and Therapeutic Perspectives.

PGAP2 gene has been known to be the cause of "hyperphosphatasia, mental retardation syndrome-3" (HPMRS3). To date, 14 pathogenic variants in PGAP2 have been identified as the cause of this syndrome in 24 patients described in single-case reports or small clinical series with pan-ethnic distribution. We aim to present a pediatric PGAP2-mutated case, intending to further expand the clinical phenotype of the syndrome and to report our experience on a therapeutic approach to drug-resistant epilepsy.We present the clinical, neuroradiological, and genetic characterization of a Caucasian pediatric subject with biallelic pathogenic variants in the PGAP2 gene revealed by next generation sequencing analysis.We identified a subject who presented with global developmental delay and visual impairment. Brain magnetic resonance imaging showed mild hypoplasia of the inferior cerebellar vermis and corpus callosum and mild white matter reduction. Laboratory investigations detected an increase in alkaline phosphatase. At the age of 13 months, he began to present epileptic focal seizures with impaired awareness, which did not respond to various antiseizure medications. Electroencephalogram (EEG) showed progressive background activity disorganization and multifocal epileptic abnormalities. Treatment with high-dose pyridoxine showed partial benefit, but the persistence of seizures and the lack of EEG amelioration prompted us to introduce ketogenic diet treatment.Our case provides a further phenotypical expansion of HPMRS3 to include developmental and epileptic encephalopathy. Due to the limited number of patients reported so far, the full delineation of the clinical spectrum of HPMRS3 and indications for precision medicine would benefit from the description of new cases and their follow-up evaluations.

Chromatin remodeler Arid1a regulates subplate neuron identity and wiring of cortical connectivity.

Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation ("handshake"), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.

Keratosis Pilaris and its Subtypes: Associations, New Molecular and Pharmacologic Etiologies, and Therapeutic Options.

Keratosis pilaris is a common skin disorder comprising less common variants and rare subtypes, including keratosis pilaris rubra, erythromelanosis follicularis faciei et colli, and the spectrum of keratosis pilaris atrophicans. Data, and critical analysis of existing data, are lacking, so the etiologies, pathogeneses, disease associations, and treatments of these clinical entities are poorly understood. The present article aims to fill this knowledge gap by reviewing literature in the PubMed, EMBASE, and CINAHL databases and providing a comprehensive, analytical summary of the clinical characteristics and pathophysiology of keratosis pilaris and its subtypes through the lens of disease associations, genetics, and pharmacologic etiologies. Histopathologic, genomic, and epidemiologic evidence points to keratosis pilaris as a primary disorder of the pilosebaceous unit as a result of inherited mutations or acquired disruptions in various biomolecular pathways. Recent data highlight aberrant Ras signaling as an important contributor to the pathophysiology of keratosis pilaris and its subtypes. We also evaluate data on treatments for keratosis pilaris and its subtypes, including topical, systemic, and energy-based therapies. The effectiveness of various types of lasers in treating keratosis pilaris and its subtypes deserves wider recognition.

Ameliorative effects of supplemental folinic acid on Lamotrigine-induced fetal malformations in the mouse.

Data from our previous work indicate that Lamotrigine (LTG) is teratogenic in the mouse. In the present study, we attempted to determine the possible protective effects of exogenous folate on LTG-induced fetal anomalies in TO mouse. Experiment I entailed administering 4 mg/kg of folinic acid (FA) and (25 mg/kg) of LTG intraperitoneally three times on gestation day (GD) 8 to a group of mice; other groups were a group that received similar volumes of saline, a group that received LTG and Saline, a group that received FA and saline. Experiment 2 involved administering groups of mice with daily 3 doses FA (or proportionate volume of saline) on GD 5 through 10 and either 3 doses of saline on GD8, or 3 doses of LTG on GD8. Maternal plasma concentrations of FA, vitamin B12 and homocysteine were determined an hour after the last injection from one-half of all animals. The other half were allowed to go to term (GD18) when they were euthanized and their fetuses were examined for visceral and skeletal malformations. A high incidence of resorption, abortion, embryolethality, congenital malformations, and intrauterine growth restriction (IUGR), was observed in the LTG-treated group. Folic acid and B12 levels were decreased and homocysteine concentration increased significantly in LTG groups. Mice receiving LTG with FA had normal levels of folate, Vitamin B12 and homocysteine levels, and the fetuses had fewer birth defects similar to the controls which were given saline only. Supplemental FA ameliorated to a great extent the LTG-induced embryonic resorption and malformations and restored the FA status.

Perfil epidemiológico da criança e do adolescente com fissura oral atendidos em um centro de referência em Curitiba, PR, Brasil / Epidemiological profile of children and adolescents with oral cleft treated at a referral center in Curitiba, PR, Brazil

INTRODUÇÃO: A fissura oral é a segunda maior causa de anomalias congênitas e representa a principal alteração craniofacial em nascidos vivos. O objetivo do presente estudo foi determinar os dados epidemiológicos do Centro de Atenção Integral ao Fissurado Labiopalatal, no período entre janeiro de 2011 e dezembro de 2014. MÉTODOS: Estudo retrospectivo utilizando prontuários clínicos. Foram avaliados 1262 prontuários de pacientes portadores de fissura oral. Após aplicação dos critérios de inclusão e exclusão, 52,7% prontuários foram incluídos no estudo. RESULTADOS: Entre os 666 prontuários, 57,4% foram do gênero masculino e 42,6% do feminino. Verificou-se que 34,8% dos pacientes apresentaram fissuras transforame, 27,2% fissuras pré-forame, 25,8% fissuras pós-forame e 12,2% outros tipos de fissuras. Pacientes oriundos de Curitiba e Região Metropolitana correspondem a 36,6%, aqueles do Interior do Paraná abrangem 61% dos atendimentos no Centro de Atenção. As medianas de idade na primeira consulta, entre os pacientes de Curitiba e Região Metropolitana e do Interior do Paraná, são de 1 mês e 2 meses, respectivamente. E a primeira cirurgia, realizada no Centro de Atenção, foi em torno de 6 meses, nos pacientes de Curitiba e Região Metropolitana, e de 7 meses naqueles oriundos do Interior do Paraná. CONCLUSÃO: Verificou-se predomínio de fissuras em meninos e maior frequência da fissura pós-forame incompleta. Observou-se que, apesar da distância, as crianças oriundas do Interior do Paraná realizaram a cirurgia de correção e chegaram ao centro de referência com apenas um mês de diferença em relação aquelas da cidade sede do Centro de Atenção Integral ao Fissurado Labiopalatal.

INTRODUCTION: Oral cleft is the second major cause of congenital anomalies and represents a major craniofacial alteration in live births. The objective of this study was to analyze the epidemiological data collected from the Center for Comprehensive Care to Individuals with Cleft Lip and Palate in the period from January 2011 to December 2014. METHODS: This retrospective study evaluated 1,262 medical records of patients with an oral cleft. After applying the inclusion and exclusion criteria, 52.7% of the medical records were included in the study. RESULTS: Among the 666 medical records, 57.4% were of male patients and 42.6% were of female patients. Of these, 34.8% of the patients had a trans-foramen cleft, 27.2% had a pre-foramen cleft, 25.8% had a post-foramen cleft, and 12.2% had another type of cleft. Patients from Curitiba and the metropolitan region constituted 36.6% of the cases, and patients from rural areas of Paraná represented 61% of the visits to the care center. The median age at the first visit of the patients from Curitiba/metropolitan region and rural areas of Paraná was 1 and 2 months, respectively. The first surgery was performed at the care center at the age of 6 months in patients from Curitiba and metropolitan region and 7 months in patients from rural areas of Paraná. CONCLUSION: There was a predominance of boys and a higher prevalence of incomplete post-foramen clefts in the total population. Despite the long distance to the care center, children from rural areas of Paraná underwent the correction surgery and were treated at the referral center with an age difference of only 1 month compared with patients who lived in Curitiba, where the care center is located.

LRRK2 knockdown in zebrafish causes developmental defects, neuronal loss, and synuclein aggregation.

Although mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinson's disease, their function is largely unknown. LRRK2 is pleiotropic in nature, shown to be involved in neurodegeneration and in more peripheral processes, including kidney functions, in rats and mice. Recent studies in zebrafish have shown conflicting evidence that removal of the LRRK2 WD40 domain may or may not affect dopaminergic neurons and/or locomotion. This study shows that ∼50% LRRK2 knockdown in zebrafish causes not only neuronal loss but also developmental perturbations such as axis curvature defects, ocular abnormalities, and edema in the eyes, lens, and otic vesicles. We further show that LRRK2 knockdown results in significant neuronal loss, including a reduction of dopaminergic neurons. Immunofluorescence demonstrates that endogenous LRRK2 is expressed in the lens, brain, heart, spinal cord, and kidney (pronephros), which mirror the LRRK2 morphant phenotypes observed. LRRK2 knockdown results further in the concomitant upregulation of ß-synuclein, PARK13, and SOD1 and causes ß-synuclein aggregation in the diencephalon, midbrain, hindbrain, and postoptic commissure. LRRK2 knockdown causes mislocalization of the Na(+) /K(+) ATPase protein in the pronephric ducts, suggesting that the edema might be linked to renal malfunction and that LRRK2 might be associated with pronephric duct epithelial cell differentiation. Combined, our study shows that LRRK2 has multifaceted roles in zebrafish and that zebrafish represent a complementary model to further our understanding of this central protein. © 2016 Wiley Periodicals, Inc.

The Buschke-Ollendorff syndrome: a case report of simultaneous osteo-cutaneous malformations in the hand.

BACKGROUND: We describe a male with functionally impairing radial deviation of the thumb who presented to us at 24 years of age. Two sclerotic skin lesions had been excised 7 years before because of consecutive skin contracture. Latest radiological examination showed a spotted pattern consistent with osteopoikilosis. CASE PRESENTATION: A corrective osteotomy of the thumb was carried out due to the patients discomfort. Facing the simultaneous osteo-cutaneous malformation we postulated a Buschke-Ollendorff syndrome. Buschke-Ollendorff syndrome is a rare autosomal-dominant hereditary disorder of connective tissue with typical osteo-cutaneous manifestations. To explore our hypothesis, biopsies were taken from the affected bone lesions and surrounding skin and soft tissue for histological investigation and genetic testing of the LEMD3 gene was performed on blood of the patient. The histology showed typical changes of the bone architecture and a fibrotic collagenous nodule of the skin. The genetic testing on DNA extracted from peripheral blood leucocytes confirmed a heterozygous loss of function mutation in the LEM domain-containing protein 3 (LEMD3) gene coding for the inner nuclear membrane protein MAN1, which causes osteopoikilosis by antagonizing transforming growth factor ß (TGF-ß) and bone morphogenetic protein (BMP) signalling. CONCLUSIONS: In atypical cases of simultaneous occurrence of fibrotic skin lesions and a spotted pattern in the X-ray we recommend the genetic screening of the LEMD3 gene. A correct diagnosis of Buschke-Ollendorff syndrome is necessary to spare patients from expensive investigations and to provide reassurance about the benign nature of the disease.

Role of bath psoralen plus ultraviolet A in early-stage mycosis fungoides.

BACKGROUND: Psoralen plus ultraviolet (UV) A (PUVA) radiation is the preferred treatment for folliculotropic mycosis fungoides (MF) and MF refractory to narrowband (NB) UVB radiation. However, systemic PUVA has many unfavorable side effects and contraindications. Bath PUVA has been found to be a suitable alternative in patients with psoriasis, but data on MF are sparse. OBJECTIVE: The purpose of the study was to evaluate the effectiveness of bath PUVA in the treatment of folliculotropic MF and NB-UVB-refractory early-stage MF. METHODS: The study group included 26 patients of average age 44 years attending a tertiary medical center in 2004 through 2012, 14 with folliculotropic type and 12 with NB-UVB-refractory early-stage MF who were not amenable for oral PUVA. Treatment consisted of 0.2 mg/L 8-methoxypsoralen bath 3 times weekly followed by UVA irradiation at 0.3 J/cm(2) with fixed increments every second session. RESULTS: A complete clinical response was achieved in 62% of patients after an average of 33 weeks and a cumulative radiation dose of 158 J/cm(2). LIMITATIONS: This was a relatively small series. CONCLUSION: Bath PUVA is a good treatment option for superficial folliculotropic MF and NB-UVB-refractory early-stage MF.

Photopneumatic therapy for the treatment of keratosis pilaris.

BACKGROUND: Current treatment options for keratosis pilaris (KP) are limited and are often found to be unsatisfactory to patients. OBJECTIVE: Pilot study to determine if photopneumatic therapy (PPx) can improve the erythema and skin texture in KP. METHODS: Ten patients with KP were treated with one session of PPx on the upper arm and then evaluated one month later for treatment efficacy. RESULTS: Average investigator-assessed improvement was 27% in erythema and 56% in skin texture roughness. Average patient self-reported improvement was 52% in erythema and 53% in skin texture. The mean satisfaction score was 6.3 on a scale of 1 to 10 (median 7.5) and 8 out of 10 participants reported they would choose to receive PPx for their KP again in the future. LIMITATIONS: Small number of patients, short follow-up period, and lack of blinding of the examiner and the patients making recall bias possible. CONCLUSIONS: One treatment of PPx improved both the erythema and redness associated with KP over at least a one month period.

The hypothetical role of congenital hypotonia in the development of early coronoid hyperplasia.

BACKGROUND: Coronoid hyperplasia (CH) is an abnormal bony elongation of a histologically normal coronoid process. Its definitive cause remains unknown. OBJECTIVES: To analyze the possible implication of congenital hypotonia in the pathogenesis of early coronoid overgrowth. PATIENTS AND METHODS: Two infants with congenital hypotonia were evaluated for limited mouth aperture. Bilateral CH was diagnosed. Transoral coronoidectomy was followed by an early dynamic physiotherapy program. RESULTS: Significant improvement of maximum interincisal opening was achieved. The review of the scientific literature proved the diagnosis of CH in the infant age group is extremely unusual and the etiology of the condition is still uncertain. CONCLUSIONS: Besides mouth opening restriction, clinical features of coronoid hyperplasia in infants can include suction or deglutition anomalies, failure to thrive and recurrent episodes of choking or aspiration pneumonia. The authors hypothesize reduced fetal mandibular movements and deglutition as a result of congenital hypotonia may lead to relative hyperactivity of the temporalis muscle that is not counterbalanced by the infra and suprahyoid muscles, thereby facilitating coronoid overgrowth.

Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome.

BACKGROUND AND OBJECTIVES: Matrix γ-carboxyglutamate protein (MGP), a vitamin K-dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an opportunity to investigate the functions of MGP. The purpose of this study was (i) to investigate the phenotype and the underlying MGP mutation of a newly identified KS patient, and (ii) to investigate MGP species and the effect of vitamin K supplements in KS patients. METHODS: The phenotype of a newly identified KS patient was characterized with specific attention to signs of vascular calcification. Genetic analysis of the MGP gene was performed. Circulating MGP species were quantified and the effect of vitamin K supplements on MGP carboxylation was studied. Finally, we performed immunohistochemical staining of tissues of the first KS patient originally described focusing on MGP species. RESULTS: We describe a novel homozygous MGP mutation (c.61+1G>A) in a newly identified KS patient. No signs of arterial calcification were found, in contrast to findings in MGP knockout mice. This patient is the first in whom circulating MGP species have been characterized, showing a high level of phosphorylated MGP and a low level of carboxylated MGP. Contrary to expectations, vitamin K supplements did not improve the circulating carboxylated mgp levels. phosphorylated mgp was also found to be present in the first ks patient originally described. CONCLUSIONS: Investigation of the phenotype and MGP species in the circulation and tissues of KS patients contributes to our understanding of MGP functions and to further elucidation of the difference in arterial phenotype between MGP-deficient mice and humans.

Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions.

Patients with Kallmann syndrome (KS) have hypogonadotropic hypogonadism caused by a deficiency of gonadotropin-releasing hormone (GnRH) and a defective sense of smell related to olfactory bulb aplasia. Based on the findings in a fetus affected by the X chromosome­linked form of the disease, it has been suggested that hypogonadism in KS results from the failed embryonic migration of neuroendocrine GnRH1 cells from the nasal epithelium to the forebrain. We asked whether this singular observation might extend to other developmental disorders that also include arrhinencephaly. We therefore studied the location of GnRH1 cells in fetuses affected by different arrhinencephalic disorders, specifically X-linked KS, CHARGE syndrome, trisomy 13, and trisomy 18, using immunohistochemistry. Few or no neuroendocrine GnRH1 cells were detected in the preoptic and hypothalamic regions of all arrhinencephalic fetuses, whereas large numbers of these cells were present in control fetuses. In all arrhinencephalic fetuses, many GnRH1 cells were present in the frontonasal region, the first part of their migratory path, as were interrupted olfactory nerve fibers that formed bilateral neuromas. Our findings define a pathological sequence whereby a lack of migration of neuroendocrine GnRH cells stems from the primary embryonic failure of peripheral olfactory structures. This can occur either alone, as in isolated KS, or as part of a pleiotropic disease, such as CHARGE syndrome, trisomy 13, and trisomy 18.

Study of smell and reproductive organs in a mouse model for CHARGE syndrome.

CHARGE syndrome is a multiple congenital anomaly syndrome characterised by Coloboma, Heart defects, Atresia of choanae, Retardation of growth and/or development, Genital hypoplasia, and Ear anomalies often associated with deafness. It is caused by heterozygous mutations in the CHD7 gene and shows a highly variable phenotype. Anosmia and hypogonadotropic hypogonadism occur in the majority of the CHARGE patients, but the underlying pathogenesis is unknown. Therefore, we studied the ability to smell and aspects of the reproductive system (reproductive performance, gonadotropin-releasing hormone (GnRH) neurons and anatomy of testes and uteri) in a mouse model for CHARGE syndrome, the whirligig mouse (Chd7(Whi/+)). We showed that Chromodomain Helicase DNA-binding protein 7 (Chd7) is expressed in brain areas involved in olfaction and reproduction during embryonic development. We observed poorer performance in the smell test in adult Chd7(Whi/+) mice, secondary either to olfactory dysfunction or to balance disturbances. Olfactory bulb and reproductive organ abnormalities were observed in a proportion of Chd7(Whi/+) mice. Hypothalamic GnRH neurons were slightly reduced in Chd7(Whi/+) females and reproductive performance was slightly less in Chd7(Whi/+) mice. This study shows that the penetrance of anosmia and hypogonadotropic hypogonadism is lower in Chd7(Whi/+) mice than in CHARGE patients. Interestingly, many phenotypic features of the Chd7 mutation showed incomplete penetrance in our model mice, despite the use of inbred, genetically identical mice. This supports the theory that the extreme variability of the CHARGE phenotype in both humans and mice might be attributed to variations in the fetal microenvironment or to purely stochastic events.

Effect of the herbal medicine dai-kenchu-to on gastrointestinal motility in patients with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) and chronic idiopathic intestinal pseudo-obstruction (CIIP): report of two cases.

Dai-kenchu-to (DKT), a traditional Japanese herbal medicine (Kampo medicine), composed of zanthoxylum fruit, ginseng root, dried ginger rhizome and malt sugar, is clinically effective for postoperative ileus and chronic constipation. MMIHS and CIIP are severe motility disorder associated with high morbidity. The aim of this study was to evaluate the effect of DKT on functional intestinal obstruction. DKT was clinically effective for gastrointestinal motility in a case with MMIHS, but not effective in one with CIIP. MMIHS and CIIP are speculated to have different pathogenesis regarding gastrointestinal pseudo-obstruction based upon the effect of this drug.

Sotos syndrome.

Sotos syndrome is an overgrowth condition characterized by cardinal features including excessive growth during childhood, macrocephaly, distinctive facial gestalt and various degrees of learning difficulty, and associated with variable minor features. The exact prevalence remains unknown but hundreds of cases have been reported. The diagnosis is usually suspected after birth because of excessive height and occipitofrontal circumference (OFC), advanced bone age, neonatal complications including hypotonia and feeding difficulties, and facial gestalt. Other inconstant clinical abnormalities include scoliosis, cardiac and genitourinary anomalies, seizures and brisk deep tendon reflexes. Variable delays in cognitive and motor development are also observed. The syndrome may also be associated with an increased risk of tumors. Mutations and deletions of the NSD1 gene (located at chromosome 5q35 and coding for a histone methyltransferase implicated in transcriptional regulation) are responsible for more than 75% of cases. FISH analysis, MLPA or multiplex quantitative PCR allow the detection of total/partial NSD1 deletions, and direct sequencing allows detection of NSD1 mutations. The large majority of NSD1 abnormalities occur de novo and there are very few familial cases. Although most cases are sporadic, several reports of autosomal dominant inheritance have been described. Germline mosaicism has never been reported and the recurrence risk for normal parents is very low (<1%). The main differential diagnoses are Weaver syndrome, Beckwith-Wiedeman syndrome, Fragile X syndrome, Simpson-Golabi-Behmel syndrome and 22qter deletion syndrome. Management is multidisciplinary. During the neonatal period, therapies are mostly symptomatic, including phototherapy in case of jaundice, treatment of the feeding difficulties and gastroesophageal reflux, and detection and treatment of hypoglycemia. General pediatric follow-up is important during the first years of life to allow detection and management of clinical complications such as scoliosis and febrile seizures. An adequate psychological and educational program with speech therapy and motor stimulation plays an important role in the global development of the patients. Final body height is difficult to predict but growth tends to normalize after puberty.

Duplication of distal 20q: clinical, cytogenetic and array CGH. Characterization of a new case.

Trisomy of the long arm of chromosome 20 is rare. We describe an 18-month-old male who was born at 36 weeks via Caesarian section after an uneventful pregnancy. During the newborn period he was found to have a right-sided cleft lip and cleft palate, hypertelorism, strabismus and mildly over-folded ears with cupping. Cardiovascular examination was consistent with the diagnosis of severe aortic coarctation, which was confirmed by echocardiogram. Additionally, hypothyroidism was diagnosed. Neurological evaluation at 18 months revealed a hypotonic infant with delayed acquisition of motor milestones. Cytogenetic analysis showed additional material on the long arm of chromosome 20, confirmed by fluorescence in situ hybridization (FISH) analysis as being of chromosome 20 origin. Because of the indistinct GTG-banding pattern it was not possible to distinguish between a proximal [dup(20)(q11.2q13.1)] or distal duplication [dup(20)(q13.1q13.3)]. To further define the duplication we used array comparative genomic hybridization (CGH) which demonstrated a 7.8 Mb interstitial duplication in distal 20q. Thus, the proband's karyotype was interpreted as 46,XY,dup(20)(q13.2q13.2). The proband is the first reported case of a pure duplication of this region. This case further highlights the utility of array CGH in characterizing aneusomies and, in particular, for accurate breakpoint designation and quantitation of ambiguous rearrangements.

Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy.

Members of the type IV collagen family are essential components of all basement membranes (BMs) and define structural stability as well as tissue-specific functions. The major isoform, alpha1.alpha1.alpha2(IV), contributes to the formation of many BMs and its deficiency causes embryonic lethality in mouse. We have identified an allelic series of three ENU induced dominant mouse mutants with missense mutations in the gene Col4a1 encoding the alpha1(IV) subunit chain. Two severe alleles (Bru and Svc) have mutations affecting the conserved glycine residues in the Gly-Xaa-Yaa collagen repeat. Bru heterozygous mice display defects similar to Axenfeld-Rieger anomaly, including iris defects, corneal opacity, vacuolar cataracts, significant iris/corneal adhesions, buphthalmos and optic nerve cupping, a sign indicative of glaucoma. Kidneys of Bru mice have peripheral glomerulopathy characterized by hypertrophy and hyperplasia of the parietal epithelium of Bowman's capsule. A milder allele (Raw) contains a mutation in the Yaa residue of the collagen repeat and was identified by a silvery appearance of the retinal arterioles. All phenotypes are associated with BM defects that affect the eye, kidney and other tissues. This allelic series shows that mutations affecting the collagen domain cause dominant negative effects on the expression and function of the major collagen IV isoform alpha1(IV), and pathological effects vary with the individual mutations.

Reported multivitamin consumption and the occurrence of multiple congenital anomalies.

The purpose of this case-control study was to determine whether multivitamin use is associated with the occurrence of multiple congenital anomalies (MCA). MCA case-infants were infants with two or more major birth defects affecting at least two different organ systems, with no recognized chromosome abnormality or single gene disorder. Control-infants were a random sample of live births with no major birth defects from the same population (metropolitan Atlanta) and time period (1993-1997) as the case-infants. Exposure to multivitamins, cereals, and supplements was ascertained from a maternal telephone interview and classified based on folic acid content. We compared women who used multivitamins three or more times per week with women who were not exposed to vitamins/cereals/supplements during the periconceptional period (3 months before pregnancy through the first trimester), adjusting for maternal age, education, race/ethnicity, first degree family history of a major birth defect, pre-pregnancy maternal body mass index, gravidity, and first trimester alcohol use and cigarette smoking. Periconceptional multivitamin use was associated with MCA among all infants (adjusted odds ratio [aOR]=2.4, 95% confidence interval [CI] 0.9-6.7), and especially when analysis was limited to those with no family history of major defects (aOR=4.0, 95% CI 1.3-12.8). MCA-infants with urinary obstructive defects were more common among multivitamin-exposed infants than among unexposed infants, but this defect did not occur within a consistent pattern of defects. While these findings provide some support for one previous study, the interpretation remains unclear given the proven protective effect of multivitamins containing folic acid on isolated neural tube defects and possibly other types of defects.

Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome in triplets.

We report female triplets with the clinical and biochemical manifestations of hypoparatyroidism-retardation-dysmorphism (HRD) syndrome also known as Sanjad-Sakati syndrome. They were born at 35 weeks gestation after assisted pregnancy (in vitro fertilization). The parents are first degree cousins from Saudi Arabia.