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The microcephaly-capillary malformation (MIC-CAP) syndrome is a life-threatening disease caused by biallelic mutations of the STAMBP gene, which encodes an endosomal deubiquitinating enzyme. To establish a suitable preclinical animal model for clinical therapeutic practice, we generated a central nervous system (CNS)-specific Stambp knockout mouse model (Stambp  Sox1-cKO ) that phenocopies Stambp null mice including progressive microcephaly, postnatal growth retardation and complete penetrance of preweaning death. In this MIC-CAP syndrome mouse model, early-onset neuronal death occurs specifically in the hippocampus and cortex, accompanied by aggregation of ubiquitinated proteins, and massive neuroinflammation. Importantly, neonatal AAV9-mediated gene supplementation of Stambp in the brain could significantly improve neurological defects, sustain growth, and prolong the lifespan of Stambp Sox1-cKO mice. Together, our findings reveal a central role of brain defects in the pathogenesis of STAMBP deficiency and provide preclinical evidence that postnatal gene replacement is an effective approach to cure the disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Human brain organoids represent a remarkable platform for modelling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses revealed that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays revealed that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Zika virus (ZIKV), a flavivirus associated with neurological disorders, constitutes a global health threat. During pregnancy, ZIKV traverses the placenta and causes congenital disease such as microcephaly and Guillain-Barré syndrome in newborns. To develop a specific antiviral therapy against ZIKV-induced microcephaly that could cross placental and blood-brain barriers, we designed targeted small extracellular vesicles (sEVs) encapsulating antiviral siRNA (small interfering RNA) to inhibit ZIKV. The neuro-specific targeting was achieved by engineering EVs membrane protein lamp2b fused with a neuron-specific rabies virus glycoprotein derived peptide (RVG). Intravenous administration of the RVG-engineered sEVs loaded with siRNA (ZIKV-specific siRNA) protected pregnant AG6 mice against vertical transmission of ZIKV. Particularly, sEVs RVG -siRNA traversed placental and blood-brain barriers and suppressed ZIKV infection in fetal brains. Moreover, sEVs RVG -siRNA alleviated the neuroinflammation and neurological damage caused by ZIKV in the fetal mouse model. In general, we developed a sEVs-based targeted system of antiviral therapy for brain and fetal brain infections., Competing Interests: Declaration of interests The authors have declared no conflict of interest., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

The Zika epidemic brought to the fore the birth of children with unknown and unexpected needs that demand longitudinal follow-up, strengthening the bond, comprehensiveness and coordination of care in health, which are essential attributes of primary health care (PHC). This article aims to evaluate the orientation of PHC care, using the PCATool-Brasil. The data were collected between 2016 and 2019, by means of interviews with parents of children who were born in a public maternity hospital in Recife (state of Pernambuco) between October 2015 and February 2016, a critical period of the microcephaly outbreak, especially in the Northeast of Brazil. The parents of 109 children participated in the survey, 15.6% of which had a confirmed microcephaly diagnosis. The degree of affiliation and access was sufficient, but the aspects of coordination of care, longitudinality, comprehensiveness, family and community orientation were insufficient. In the context of congenital Zika syndrome, these attributes are essential for the care of children and families. The fostering of health from these domains depends on the orientation of the models of care and their management with state and federal investments. The defense of life depends on the ability to place life above all other rationalities.

Congenital Zika Syndrome (CZS) is characterized by changes in cranial morphology associated with heterogeneous neurological manifestations and cognitive and behavioral impairments. In this syndrome, longitudinal neuroimaging could help clinicians to predict developmental trajectories of children and tailor treatment plans accordingly. However, regularly acquiring magnetic resonance imaging (MRI) has several shortcomings besides cost, particularly those associated with childrens' clinical presentation as sensitivity to environmental stimuli. The indirect monitoring of local neural activity by non-invasive functional near-infrared spectroscopy (fNIRS) technique can be a useful alternative for longitudinally accessing the brain function in children with CZS. In order to provide a common framework for advancing longitudinal neuroimaging assessment, we propose a principled guideline for fNIRS acquisition and analyses in children with neurodevelopmental disorders. Based on our experience on collecting fNIRS data in children with CZS we emphasize the methodological challenges, such as clinical characteristics of the sample, desensitization, movement artifacts and environment control, as well as suggestions for tackling such challenges. Finally, metrics based on fNIRS can be associated with established clinical metrics, thereby opening possibilities for exploring this tool as a long-term predictor when assessing the effectiveness of treatments aimed at children with severe neurodevelopmental disorders., (© 2021. The Author(s).)

Rationale: Wiedemann-Steiner syndrome (WDSTS, online mendelian inheritance in man 605130) is a rare autosomal dominant disorder characterized by hypertrichosis cubiti. Here, we report a Chinese boy who do not show the characteristic of hypertrichosis cubiti, and was misdiagnosed as blepharophimosis-ptosis-epicanthus inversus syndrome at first. We found a de novo frameshift mutation (p.Glu390Lysfs*10) in the KMT2A gene, which was not reported before. Our study increases the cohort of Chinese WDSTS patients, and expand the WDSTS phenotypic and variation spectrum., Patient Concerns: The patient demonstrated typical craniofacial features of blepharophimosis-ptosis-epicanthus inversus syndrome, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, besides he had congenital heart disease (ventricular septal defects), strabismus, hypotonia, amblyopia, delayed speech and language development, delayed psychomotor development, and amblyopia (HP:0000646) which was not reported before., Diagnosis: FOXL2 gene was cloned and sequenced, however, there was no mutation detected in this patient. The result of Chromosomal microarray analysis was normal. The patient was diagnosed as WDSTS by whole exome sequencing., Interventions: The patient received cardiac surgery, frontalis suspension and regular speech and occupational therapy. He also treated with growth hormone (GH)., Outcomes: The patient's symptoms are improved after cardiac surgery and frontalis suspension, he can express himself well now and had a 10 cm gain in height., Lessons: As the relationship between genotype and phenotype becomes more and more clear, WES is incredibly powerful tool to diagnose the disease of WDSTS.

Objective: To know the maternal perception about early stimulation and its repercussion in the development of the child with microcephaly associated with zika virus., Method: A qualitative study was carried out from June to August 2017 with five mothers of children diagnosed with microcephaly associated with zika virus. The data were collected through individual interviews with semi-structured script and evaluated by the content analysis, in its thematic modality., Results: Mothers recognized the benefits and the advances in the development of the child after the beginning of the early stimulation. It is noteworthy that the difficulty of transportation was the main reason for the lack of attendance at consultations, and that the short time of stimulation was the main weakness of the service., Final Considerations: The recognition of maternal perception and the difficulties and weaknesses of the service can contribute to the elaboration of public policies and the planning of holistic care for children with microcephaly and their families.

Objective: To report the educational experiences of mothers or caregivers of children with microcephaly, as developed by an academic team with the theme of promoting these children's health., Method: This is an experience report by undergraduate nursing students and Health and Environment Post-Graduation students and professors of Tiradentes University on educational interventions carried out in three reference units for the care of children with microcephaly in the state of Sergipe. The study sample was taken by convenience., Results: A total of 70 mothers or primary caregivers of children with a confirmed diagnosis of microcephaly during the months of September to December participated in the study. The thematic-theoretical axes selected to describe the activities were promotion of healthy eating, importance of the mother and child bond, and early stimulation of children with microcephaly., Conclusion: The experience reported demonstrates the importance of educational strategies in promoting the health of children with microcephaly, providing additional training to mothers/caregivers to provide holistic and humanized care to these children.

Hoyeraal-Hreidarsson syndrome (HHS), caused by several different germline mutations resulting in severe telomeropathy, presents with early-onset growth anomalies and neurologic/developmental disorders including characteristic cerebellar hypoplasia. Early mortalities may arise from immunodeficiency and bone marrow failure if not successfully salvaged by allogeneic hematopoietic stem cell transplantation (HSCT). Few reports have characterized the persistent somatic progression of HHS after successful HSCT. We present an HHS patient with an X-linked recessive DKC1 c.1058C > T; Ala353Val mutation who successfully underwent unrelated HSCT at 5 years of age. After months of early infections and organ toxicities immediately post-transplant, he had more than two years of excellent quality of life with correction of bone marrow failure and immunodeficiency. However, episodic massive variceal bleeding and progressive respiratory insufficiency, which were secondary to non-cirrhotic portal hypertension and pulmonary arteriovenous shunts, respectively, developed over 2 years after HSCT and resulted in his death from respiratory failure 4 years after HSCT. This outcome suggests that while HSCT can correct bone marrow failure and immunodeficiency, it may fail to prevent or even aggravate other fatal processes, such as portal hypertension and pulmonary arteriovenous shunting.

Background: Children with microcephaly due to vertical exposure to Zika virus are an interesting population for investigation. Highlighted among their unique aspects are those related to nutrition due to its impact on child growth and development. Knowledge about the nutrition of microcephalic infants can help mothers and caregivers provide better care. Thus, this study aimed to describe the nutritional status and feeding practices of infants with microcephaly due to Zika virus exposure at birth and 12-23 months of age., Methods: This is a descriptive study developed from a cohort of patients attending a public institution of reference. A total of 65 infants attended outpatient nutrition clinics. The food practices were described using the 24-h food recall and food consumption indicators. Anthropometric measurements and consultations were made using the Child Health Handbook to obtain information on the nutritional status (weight, height and head circumference) at the time of consultation and birth., Results: There was a significant decrease in z-scores for weight, height and head circumference (HC) from birth to the time of the consultation. However, most infants did not show weight-for-height deficits. Additionally, HC was correlated with the anthropometric indices weight-for-age, height-for-age, body mass index-for-age and weight-for-height., Conclusion: Infants exhibited a worsening of their nutritional status between birth and the time of their consultation, notably when we evaluated the indices of height and head circumference for age. The main inadequacies regarding dietary practices were low food diversity, use of ultra-processed products and low lipid intake.

Dubowitz syndrome was described in 1965 as a recognizable syndrome characterized by microcephaly, short stature, eczema, mild developmental delays, and an increased risk of malignancy. Since its original description, there have been over 200 reported cases though no single gene has been identified to explain a significant proportion of affected individuals. Since the last definitive review of Dubowitz syndrome in 1996, there have been 63 individuals with a clinical, or suspected, diagnosis of Dubowitz syndrome reported in 51 publications. These individuals show a markedly wide spectrum with respect to growth, facial gestalt, psychomotor development, and risk of malignancy; genetic causes were identified in 33% (21/63). Seven individuals had deleterious copy number variants, in particular deletions at 14q32 and 17q24 were reported and showed overlap with the Dubowitz phenotype. Several cases were shown to have single gene disorders that included de novo or biallelic pathogenic variants in several genes including NSUN2 and LIG4 frequently identified by next-generation sequencing methods. It appears that the inability to identify a single gene responsible for Dubowitz syndrome reflects its extreme clinical and genetic heterogeneity. However, detailed phenotyping combined with careful grouping of subsets of unsolved cases and in conjunction with data-sharing will identify novel disease genes responsible for additional cases. In the interim, for those clinically diagnosed with a Dubowitz phenotype, we recommend assessment by a Medical Geneticist, a microarray and, if available, clinical or research based genome-wide sequencing. Management suggestions, including decisions regarding malignancy screening in select patients will be discussed., (© 2018 Wiley Periodicals, Inc.)

We have learned much about the short-term sequelae of congenital Zika virus (ZIKV) infection since the Centers for Disease Control and Prevention activated its ZIKV emergency response in January 2016. Nevertheless, gaps remain in our understanding of the full spectrum of adverse health outcomes related to congenital ZIKV infection and how to optimize health in those who are affected. To address the remaining knowledge gaps, support affected children so they can reach their full potential, and make the best use of available resources, a carefully planned public health approach in partnership with pediatric health care providers is needed. An essential step is to use population-based data captured through surveillance systems to describe congenital Zika syndrome. Another key step is using collected data to investigate why some children exhibit certain sequelae during infancy and beyond, whereas others do not, and to describe the clustering of anomalies and the timing of when these anomalies occur, among other research questions. The final critical step in the public health framework for congenital Zika syndrome is an intervention strategy with evidence-based best practices for longer-term monitoring and care. Adherence to recommended evaluation and management procedures for infants with possible congenital ZIKV infection, including for those with less obvious developmental and medical needs at birth, is essential. It will take many years to fully understand the effects of ZIKV on those who are congenitally infected; however, the lifetime medical and educational costs as well as the emotional impact on affected children and families are likely to be substantial., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies., (© 2017 Wiley Periodicals, Inc.)

Objectives: Children with microcephaly face lifelong psychomotor, cognitive, and communications skills disabilities. Etiology of microcephaly is heterogeneous but presentation often includes seizures, hypotonia, ataxia, stereotypic movements, attention deficits, excitability, cognitive delays, and poor communication skills. Molecular diagnostics have outpaced available interventions and most children receive generic physical, speech, and occupational therapies with little attention to the efficacy of such treatments. Mutations in the X-linked intellectual disability gene (XLID) CASK is one etiology associated with microcephaly which produces mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH; OMIM# 300749). We pilot-tested an intensive therapy in three girls with heterozygous mutation in the gene CASK and MICPCH. Child A = 54 months; Child B = 89 months; and Child C = 24 months received a targeted treatment to improve gross/fine motor skills, visual-motor coordination, social interaction, and communication. Treatment was 4 h each weekday for 10 treatment days. Operant training promoted/refined goal-directed activities. The Peabody Developmental Motor Scales 2 was administered pre- and post-treatment., Results: Child A gained 14 developmental months; Child B gained 20 developmental months; and Child C gained 39 developmental months. This case series suggests that children with MICPCH are responsive to intensive therapy aimed at increasing functional skills/independence. Trial Registration ClinicalTrials.gov Registration Number: NCT03325946; Release Date: October 30, 2017.

We examined longitudinal neurodevelopmental outcomes in a series of infants with microcephaly. Retrospective review identified neonatal intensive care unit follow-up clinic patients with a diagnostic code of microcephaly, verified by head circumference less than the fifth precentile (WHO growth curves). Data were collected regarding clinical history and developmental assessments by Capute Scales and gross motor age equivalent. Developmental Quotient (DQ) was age adjusted up until 2 years for preterm infants. Twenty-two infants had microcephaly. At latest follow-up (3-66 months, mean 27.2), 73% had delay (DQ < 70) in ≥1 area of development: gross motor 65% (mean DQ 56.8), visual-motor 59% (mean DQ 62.7), and language 59% (mean DQ 65.9). In this sample, postnatal onset and diagnosis of epilepsy were associated with lower DQs. We conclude that infants with microcephaly are at significant risk for delay across all aspects of development and for long-term disability. Postnatal etiologies of microcephaly and infants with comorbid epilepsy had worse outcomes.

Autosomal recessive primary microcephaly (MCPH; MicroCephaly Primary Hereditary) is a genetically heterogeneous neurodevelopmental disorder characterized by a significantly reduced head circumference present already at birth and intellectual disability. Inconsistent features include hyperactivity, an expressive speech disorder, and epilepsy. Here, we provide a brief overview on this rare disorder pertinent for clinicians., Competing Interests: Competing Interest: The authors declare that they have no competing interest., (Georg Thieme Verlag KG Stuttgart · New York.)

As of November 2016, the Florida Department of Health (FDH) and the Centers for Disease Control and Prevention have confirmed more than 4000 travel-related Zika virus (ZIKV) infections in the United States with >700 of those in Florida. There have been 139 cases of locally acquired infection, all occurring in Miami, Florida. Within the US territories (eg, Puerto Rico, US Virgin Islands), >30,000 cases of ZIKV infection have been reported. The projected number of individuals at risk for ZIKV infection in the Caribbean and Latin America approximates 5 million. Similar to Dengue and Chikungunya viruses, ZIKV is spread to humans by infected Aedes aegypti mosquitoes, through travel-associated local transmission, via sexual contact, and through blood transfusions. South Florida is an epicenter for ZIKV infection in the United States and the year-round warm climate along with an abundance of mosquito vectors that can harbor the flavivirus raise health care concerns. ZIKV infection is generally mild with clinical manifestations of fever, rash, conjunctivitis, and arthralgia. Of greatest concern, however, is growing evidence for the relationship between ZIKV infection of pregnant women and increased incidence of abnormal pregnancies and congenital abnormalities in the newborn, now medically termed ZIKA Congenital Syndrome. Federal health officials are observing 899 confirmed Zika-positive pregnancies and the FDH is currently monitoring 110 pregnant women with evidence of Zika infection. The University of Miami/Jackson Memorial Hospital is uniquely positioned just north of downtown Miami and within the vicinity of Liberty City, Little Haiti, and Miami Beach, which are currently "hot spots" for Zika virus exposure and transmissions. As the FDH works fervently to prevent a Zika epidemic in the region, health care providers at the University of Miami and Jackson Memorial Hospital prepare for the clinical spectrum of ZIKV effects as well as the safe perioperative care of the parturients and their affected newborns. In an effort to meet anesthetic preparedness for the care of potential Zika-positive patients and perinatal management of babies born with ZIKA Congenital Syndrome, this review highlights the interim guidelines from the Centers for Disease Control and Prevention and also suggest anesthetic implications and recommendations. In addition, this article reviews guidance for the evaluation and anesthetic management of infants with congenital ZIKV infection. To better manage the perioperative care of affected newborns, this article also reviews the comparative anesthetic implications of babies born with related congenital malformations.

From the discovery of the Zika virus (ZIKV) in 1947 in Uganda (Africa), until its arrival in South America, it was not known that it would affect human reproductive life so severely. Today, damage to the central nervous system is known to be multiple, and microcephaly is considered the tip of the iceberg. Microcephaly actually represents the epilogue of this infection's devastating process on the central nervous system of embryos and fetuses. As a result of central nervous system aggression by the ZIKV, this infection brings the possibility of arthrogryposis, dysphagia, deafness and visual impairment. All of these changes of varying severity directly or indirectly compromise the future life of these children, and are already considered a congenital syndrome linked to the ZIKV. Diagnosis is one of the main difficulties in the approach of this infection. Considering the clinical part, it has manifestations common to infections by the dengue virus and the chikungunya fever, varying only in subjective intensities. The most frequent clinical variables are rash, febrile state, non-purulent conjunctivitis and arthralgia, among others. In terms of laboratory resources, there are also limitations to the subsidiary diagnosis. Molecular biology tests are based on polymerase chain reaction (PCR) with reverse transcriptase (RT) action, since the ZIKV is a ribonucleic acid (RNA) virus. The RT-PCR shows serum or plasma positivity for a short period of time, no more than five days after the onset of the signs and symptoms. The ZIKV urine test is positive for a longer period, up to 14 days. There are still no reliable techniques for the serological diagnosis of this infection. If there are no complications (meningoencephalitis or Guillain-Barré syndrome), further examination is unnecessary to assess systemic impairment. However, evidence is needed to rule out other infections that also cause rashes, such as dengue, chikungunya, syphilis, toxoplasmosis, cytomegalovirus, rubella, and herpes. There is no specific antiviral therapy against ZIKV, and the therapeutic approach to infected pregnant women is limited to the use of antipyretics and analgesics. Anti-inflammatory drugs should be avoided until the diagnosis of dengue is discarded. There is no need to modify the schedule of prenatal visits for pregnant women infected by ZIKV, but it is necessary to guarantee three ultrasound examinations during pregnancy for low-risk pregnancies, and monthly for pregnant women with confirmed ZIKV infection. Vaginal delivery and natural breastfeeding are advised., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil.)

Serine biosynthesis defects can present in a broad phenotypic spectrum ranging from Neu-Laxova syndrome, a lethal disease with multiple congenital anomalies at the severe end, to an infantile disease with severe psychomotor retardation and seizures as an intermediate phenotype, to a childhood disease with intellectual disability at the mild end. In this report we present 6 individuals from 3 families with infantile phosphoglycerate dehydrogenase (PGDH) deficiency who presented with psychomotor delay, growth failure, microcephaly, and spasticity. The phenotype was variable with absence of seizures in 2 sisters in family 1 and 1 infant in family 2 and seizures with pronounced happy affect in 3 sisters in family 3. The initiation of serine treatment had pronounced effect on seizures and spasticity in the sisters in family 3, but minimal developmental effects on the children in families 1 and 2. With such phenotypic variability, the diagnosis of PGDH deficiency can be challenging.

Several recent articles published by Brain and Development in 2016 demonstrated some rare, but innovative, genetic mechanisms for microcephaly. This concise mini-review presented another novel pathogenic mechanism for microcephaly, which has actually been a worldwide medical challenge since the World Health Organization (WHO) defined the outbreak of the Zika virus (ZIKV) as an International Public Health Emergency on 1 Feb, 2016. As a recent noteworthy clinical phenomenon, the ZIKV outbreak was accompanied by a dramatically increased number of microcephalus fetuses. However, no direct evidence supporting the suspected pathogenic effects of ZIKV on fetal microcephaly was shown previously before 2016. Herein, we evaluated the most important human pathological, animal developmental, and neuro-cytotoxic findings released in 2016, and highlighted the original experimental evidence that strengthens the potential link between ZIKV and the high incidence of microcephaly in new-born babies. Because killing mosquitoes via insecticides is currently the only effective way to suppress ZIKV-induced disorders, the animal and cellular models described in this mini-review are very beneficial to anti-ZIKV drug development and vaccine assessment., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The ongoing Zika virus outbreak in South, Central, and, most recently, North America has become a global health care emergency. Originally thought to be a benign, self-limiting viral syndrome, the newest epidemic has provided convincing evidence that maternal Zika virus infection can lead to neonatal malformations, the so-called congenital Zika syndrome. The alarming number of microcephalic neonates being born during the current outbreak is most notable, though several other anomalies, such as arthrogryposis, redundant scalp tissue, and cranial collapse, have been reported. Additionally, Zika virus represents an occupational hazard to plastic and reconstructive surgeons and their teams, as well as an infectious risk to patients receiving blood and human tissue products. In this article, we aim to provide current disease-related information to help guide the practicing plastic surgeon in the safe and effective management of patients affected by congenital Zika syndrome and to educate plastic surgeons regarding occupational and transmissivity risks of Zika virus.

Purpose of the Review: This review will provide an overview of the microcephalic primordial dwarfism (MPD) class of disorders and provide the reader comprehensive clinical review with suggested care guidelines for patients with microcephalic osteodysplastic primordial dwarfism, type II (MOPDII)., Recent Findings: Over the last 15 years, significant strides have been made in the diagnosis, natural history, and management of MOPDII. MOPDII is the most common and well described form of MPD. The classic features of the MPD group are severe pre- and postnatal growth retardation, with marked microcephaly. In addition to these features, individuals with MOPDII have characteristic facies, skeletal dysplasia, abnormal dentition, and an increased risk for cerebrovascular disease and insulin resistance. Biallelic loss-of-function mutations in the pericentrin gene cause MOPDII, which is inherited in an autosomal recessive manner.

The c.2101A>G synonymous change (p.G674G) in the gene for ATR, a key player in the DNA-damage response, has been the first identified genetic cause of Seckel Syndrome (SS), an orphan disease characterized by growth and mental retardation. This mutation mainly causes exon 9 skipping, through an ill-defined mechanism. Through ATR minigene expression studies, we demonstrated that the detrimental effect of this mutation (6±1% of correct transcripts only) depends on the poor exon 9 definition (47±4% in the ATR wt context), because the change was ineffective when the weak 5' or the 3' splice sites (ss) were strengthened (scores from 0.54 to 1) by mutagenesis. Interestingly, the exonic c.2101A nucleotide is conserved across species, and the SS-causing mutation is predicted to concurrently strengthen a Splicing Silencer (ESS) and weaken a Splicing Enhancer (ESE). Consistently, the artificial c.2101A>C change, predicted to weaken the ESE only, moderately impaired exon inclusion (28±7% of correct transcripts). The observation that an antisense oligonucleotide (AON ATR ) targeting the c.2101A position recovers exon inclusion in the mutated context supports a major role of the underlying ESS. A U1snRNA variant (U1 ATR ) designed to perfectly base-pair the weak 5'ss, rescued exon inclusion (63±3%) in the ATR SS -allele. Most importantly, upon lentivirus-mediated delivery, the U1 ATR partially rescued ATR mRNA splicing (from ~19% to ~54%) and protein (from negligible to ~6%) in embryonic fibroblasts derived from humanized ATR SS mice. Altogether these data elucidate the molecular mechanisms of the ATR c.2101A>G mutation and identify two potential complementary RNA-based therapies for Seckel syndrome., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Acute hypercapnic respiratory failure is mostly seen in patients with chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome (OHS). Depending on the underlying cause it may be associated with hypoxemic respiratory failure and places high demands on mechanical ventilation., Objective: Presentation of the current knowledge on indications and management of mechanical ventilation in patients with hypercapnic respiratory failure., Material and Methods: Review of the literature., Results: Important by the selection of mechanical ventilation procedures is recognition of the predominant pathophysiological component. In hypercapnic respiratory failure with a pH < 7.35 non-invasive ventilation (NIV) is primarily indicated unless there are contraindications. In patients with severe respiratory acidosis NIV requires a skilled and experienced team and close monitoring in order to perceive a failure of NIV. In acute exacerbation of COPD ventilator settings need a long expiration and short inspiration time to avoid further hyperinflation and an increase in intrinsic positive end-expiratory pressure (PEEP). Ventilation must be adapted to the pathophysiological situation in patients with OHS or overlap syndrome. If severe respiratory acidosis and hypercapnia cannot be managed by mechanical ventilation therapy alone extracorporeal venous CO2 removal may be necessary. Reports on this approach in awake patients are available., Conclusion: The use of NIV is the predominant treatment in patients with hypercapnic respiratory failure but close monitoring is necessary in order not to miss the indications for intubation and invasive ventilation. Methods of extracorporeal CO2 removal especially in awake patients need further evaluation.

Background: Hoyeraal-Hreidarsson syndrome is a dyskeratosis congenita-related telomere biology disorder that presents in infancy with intrauterine growth retardation, immunodeficiency, and cerebellar hypoplasia in addition to the triad of nail dysplasia, skin pigmentation, and oral leukoplakia. Individuals with Hoyeraal-Hreidarsson syndrome often develop bone marrow failure in early childhood. Germline mutations in DKC1, TERT, TINF2, RTEL1, ACD, or PARN cause about 60% of individuals with Hoyeraal-Hreidarsson syndrome., Patient Description: We describe 14 years of follow-up of an individual with Hoyeraal-Hreidarsson syndrome who initially presented as an infant with intrauterine growth retardation, microcephaly, and central nervous system calcifications. He was diagnosed with Hoyeraal-Hreidarsson syndrome at age 6 years and had a complicated medical history including severe developmental delay, cerebellar hypoplasia, esophageal and urethral stenosis, hip avascular necrosis, immunodeficiency, and bone marrow failure evolving to myelodysplastic syndrome requiring hematopoietic cell transplantation at age 14 years. He had progressive skin pigmentation, oral leukoplakia, and nail dysplasia leading to anonychia. Whole exome sequencing identified novel biallelic variants in PARN., Conclusions: This patient illustrates that the constellation of intrauterine growth retardation, central nervous system calcifications, and cerebellar hypoplasia, esophageal or urethral stenosis, and cytopenias, in the absence of congenital infection, may be due to Hoyeraal-Hreidarsson syndrome. Early diagnosis of Hoyeraal-Hreidarsson syndrome is important to optimize medical management and provide genetic counseling., (Published by Elsevier Inc.)

Dyskeratosis congenita (DKC) is an inherited bone marrow failure (BMF) syndrome typified by reticulated skin pigmentation, nail dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is considered to be a severe form of DKC. Unconventional forms of DKC, which develop slowly in adulthood but without the physical anomalies characteristic of DKC (cryptic DKC), have been reported. Clinical and genetic features of DKC have been investigated in Caucasian, Black, and Hispanic populations, but not in Asian populations. The present study aimed to determine the clinical and genetic features of DKC, HHS, and cryptic DKC among Japanese patients. We analyzed 16 patients diagnosed with DKC, three patients with HHS, and 15 patients with cryptic DKC. We found that platelet count was significantly more depressed than neutrophil count or hemoglobin value in DKC patients, and identified DKC patients with large deletions in the telomerase reverse transcriptase and cryptic DKC patients with RTEL1 mutations on both alleles. This led to some patients previously considered to have unclassifiable BMF being diagnosed with cDKC through identification of new gene mutations. It thus seems important from a clinical viewpoint to re-examine the clinical characteristics, frequency of genetic mutations, and treatment efficacy in DKC, HHS, and cDKC.

Neurovascular diseases are among the leading causes of mortality and permanent disability due to stroke, aneurysm, and other cardiovascular complications. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Marfan syndrome are two neurovascular disorders that affect smooth muscle cells through accumulation of granule and osmiophilic materials and defective elastic fiber formations respectively. Moyamoya disease, hereditary hemorrhagic telangiectasia (HHT), microcephalic osteodysplastic primordial dwarfism type II (MOPD II), and Fabry's disease are disorders that affect the endothelium cells of blood vessels through occlusion or abnormal development. While much research has been done on mapping out mutations in these diseases, the exact mechanisms are still largely unknown. This paper briefly introduces the pathogenesis, genetics, clinical symptoms, and current methods of treatment of the diseases in the hope that it can help us better understand the mechanism of these diseases and work on ways to develop better diagnosis and treatment.

Objective: To provide an evidence-based update emphasizing the importance of measuring head circumference (HC) in infants, with a focus on microcephaly., Quality of Evidence: PubMed and EMBASE (OvidSP) were searched. Search terms used were head circumference and infants and measurement; microcephaly and infants and measurement; idiopathic microcephaly and infants; and congenital microcephaly and infants. Most of the references for this review were published in 2000 or later. Most evidence is level II., Main Message: Serial measurement of HC should be incorporated into routine well-child care. Measure the distance around the back of the child's head with a nonelastic tape measure held above the eyebrows and ears, and plot the measurement on an age- and sex-appropriate growth chart. Microcephaly is HC more than 2 SD below the mean. The most common disability associated with microcephaly is intellectual delay; other common concomitant conditions include epilepsy, cerebral palsy, language delay, strabismus, ophthalmologic disorders, and cardiac, renal, urinary tract, and skeletal anomalies. An interdisciplinary approach to microcephaly is warranted. Although there are no specific interventions to enhance brain growth, dietary or surgical interventions might be helpful in some cases. Infants with microcephaly who show developmental delays might benefit from early intervention programs or developmental physical and occupational therapy., Conclusion: Early identification of HC concerns by family physicians can be a critical first step in identifying disorders such as microcephaly, leading to referral to pediatric specialists and, as needed, provision of family-centred early intervention services.

Human mutations in PQBP1, a molecule involved in transcription and splicing, result in a reduced but architecturally normal brain. Examination of a conditional Pqbp1-knockout (cKO) mouse with microcephaly failed to reveal either abnormal centrosomes or mitotic spindles, increased neurogenesis from the neural stem progenitor cell (NSPC) pool or increased cell death in vivo. Instead, we observed an increase in the length of the cell cycle, particularly for the M phase in NSPCs. Corresponding to the developmental expression of Pqbp1, the stem cell pool in vivo was decreased at E10 and remained at a low level during neurogenesis (E15) in Pqbp1-cKO mice. The expression profiles of NSPCs derived from the cKO mouse revealed significant changes in gene groups that control the M phase, including anaphase-promoting complex genes, via aberrant transcription and RNA splicing. Exogenous Apc4, a hub protein in the network of affected genes, recovered the cell cycle, proliferation, and cell phenotypes of NSPCs caused by Pqbp1-cKO. These data reveal a mechanism of brain size control based on the simple reduction of the NSPC pool by cell cycle time elongation. Finally, we demonstrated that in utero gene therapy for Pqbp1-cKO mice by intraperitoneal injection of the PQBP1-AAV vector at E10 successfully rescued microcephaly with preserved cortical structures and improved behavioral abnormalities in Pqbp1-cKO mice, opening a new strategy for treating this intractable developmental disorder.

Introduction: Hirschsprung's disease (HD) or aganglionicmegacolon is a congenital disorder characterized by the absence of ganglion intramural cells of the submucosal myenteric plexus (namely Auerbach and Meissner,respectively) in distal sections of the intestine. This is due to a failure in the migration of the precursors of these cells from the neural chalk during the embryonic development and also due to other abnormalities associated(18 % of cases), in some cases involving specific polymalformation syndromes., Objectives: The aim of the work is to present the clinical and nutritional evolution of a 14 months aged pediatric patient who was diagnosed with HD since was born associated with Mowat-Wilson syndrome (MWS). In addition,it is also targeted to evaluate the clinical results from this patient., Methods: Reviewing the medical history of the patient,the evolution of the anthropometric data (weight and height) as well as the analytical parameters for further studies were carried out. In addition, the upcoming issues associated with nutritional support and therapeutic strategies in the multidisciplinary context were evaluated., Results: A male, 14 months aged patient, son of not consanguineous healthy immigrants parents from Colombia went to the emergency department of our hospital suffering abdominal distension and vomiting with no spontaneous bowels. A detailed description of the composition of parenteral nutrition administered within the period of 28 days of hospital admission., Conclusion: As observed in this patient, the association of HD and MWS can lead to the need of prolonged parenteral nutrition and frequently present diverting stoma leading to a greater number of postoperative complications in this population., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Feingold syndrome (FGLDS1) is an autosomal dominant disorder caused by mutations in the MYCN oncogene on the short arm of chromosome 2 (2p24.1). It is characterised by microcephaly, digital abnormalities, oesophageal and duodenal atresias, and often learning disability or mental retardation. In 2011, individuals sharing the skeletal abnormalities of FGLDS1 but lacking mutations in MYCN, were found to harbour hemizygous deletions of the MIR17HG gene on chromosome 13q31.3. These individuals share many of the characteristics of FGLDS1 except for gastrointestinal atresia. The condition was termed Feingold syndrome type 2 (FGLDS2). We describe the presentation and management of a fourth known case of FGLDS2 in an 18-year-old girl with microcephaly, short stature, mildly dysmorphic features, digital malformations and significant cognitive and psychiatric symptoms. Comparative genomic hybridisation array testing confirmed a 7.4 Mb microdeletion in chromosome region 13q31.1q.31.3 corresponding to the MIR17HG gene., (2014 BMJ Publishing Group Ltd.)

Raine syndrome (RS) is a bone dysplasia characterised by generalised osteosclerosis with periosteal bone formation, characteristic face, and brain abnormalities [MIM # 259775]. Its prevalence is estimated to be < 1/1,000,000. Although it was originally thought always to be lethal, there have now been six reports of patients surviving into childhood and this phenotype is still being defined. The skeletal dysplasia predominantly affects craniofacial development explaining the severe proptosis, underdeveloped midface, depressed nasal bridge and short nose. The main radiological manifestation is a diffuse, marked osteosclerosis of the base of skull and long bones. Raine syndrome is caused by biallelic mutations in FAM20C, located on chromosome 7p22.3. This gene encodes a Golgi casein kinase, which phosphorylates serine residues of extracellular proteins involved in biomineralisation. Facial appearance and radiological findings allow the clinical diagnosis, and molecular testing of FAM20C can confirm this. Desmosterolosis and congenital cytomegalovirus infection may resemble Raine syndrome. If Raine syndrome is suspected prenatally the newborn should be admitted at a neonatal intensive care unit as significant respiratory distress is often present immediately after birth. We present here a review of the pertinent literature in clinical manifestations, molecular background, diagnosis and management., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Seckel syndrome is a rare autosomal recessive disease, genetically heterogeneous, characterized by short stature, prenatal microcephaly, intellectual disability, dysmorphic features, chromosomal instability, and hematological disorders. We report the case of a six-yr-old boy with Seckel syndrome and aplastic anemia who underwent successful allogeneic bone marrow transplantation from ten of ten HLA matched unrelated donor. Currently the patient is on D+771, in good health conditions and with no further complications. In conclusion, this case indicates that bone marrow transplantation is an acceptable therapeutic option for Seckel syndrome complicated by hematological alterations., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Context: Homozygous IGF1 deletions or mutations lead to severe short stature, deafness, microcephaly, and mental retardation. Heterozygosity for an IGF-I defect may modestly decrease height and head circumference., Objective: The objective of the study was to investigate the clinical features of heterozygous carriers of a novel mutation in the IGF1 gene in comparison with noncarriers in a short family and to establish the effect of human GH treatment., Subjects: Two children, their mother, and their maternal grandfather carried the mutation and were compared with two relatives who were noncarriers., Results: The two index cases had severe short stature (height sd score -4.1 and -4.6), microcephaly, and low IGF-I levels. Sequencing of IGF1 revealed a heterozygous duplication of four nucleotides, resulting in a frame shift and a premature termination codon. The mother and maternal grandfather had the same IGF1 mutation. Adult height (corrected for shrinking and secular trend) and head circumference sd score of carriers of the paternally transmitted mutation was -2.5 and -1.8, in comparison with -1.6 and 0.3 in noncarriers, respectively. After 2 yr of GH treatment, both index cases exhibited increased growth., Conclusions: Heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation, presumably in combination with other genetic factors for short stature, leads to severe short stature, which can be successfully treated with GH.

Background: Microcephaly-lymphoedema-chorioretinal dysplasia (MLCRD) is a rare syndrome characterized by microcephaly, chorioretinal dysplasia, lymphoedema and a characteristic facial phenotype. The exact mode of inheritance is uncertain, autosomal dominant, recessive and X-chromosomal cases have been reported., History and Signs: A three-month-old boy with intrauterine growth retardation and microcephaly was referred to our clinic. The ophthalmic examination revealed a left eye with a persistent hyperplastic primary vitreous. On funduscopy of the right eye pale optic disc, chorioretinal dysplasia with pigmentary and atrophic changes and falciform folds were noted. General morphological changes and ophthalmological findings led to the diagnosis of MLCRD-syndrome., Therapy and Outcome: Eye examinations of the parents and the grandparents did not show any retinal changes, therefore an autosomal dominant inheritance was excluded., Conclusions: An ophthalmological examination in children with microcephaly and facial dysmorphies is essential. Parents and grandparents should also be considered for eye examination if a child has chorioretinal dysplasia and microcephaly.

The suspicion of an abnormality of the central nervous (CNS) system raises difficult questions for the clinician and the family and will inevitably lead to considerable anxiety. These questions include what it means for the child's future, whether it can be treated and whether it will happen again in subsequent pregnancies. For many disorders accurate prenatal diagnosis remains elusive, as even with fetal magnetic resonance imaging (MRI), early recognition and characterisation are simply not possible because of the immature state of brain development at that stage of pregnancy. The natural history of many prenatally diagnosed CNS disorders remains to be elucidated which means that an accurate prognosis cannot be given in all cases. We review the current state of knowledge regarding the investigation, management and prognosis of the most common and important CNS malformations. We also discuss the post-natal management of these conditions both in the neonate and subsequent pregnancies for the families.

The rat with micrencephaly, produced by prenatal exposure to methylazoxymethanol, provides a useful model to study neurobehavioral abnormalities associated with congenital brain defects. The micrencephalic animals have a life-long learning impairment. As they age, their already impaired learning competence deteriorates further. To determine whether the aging-associated functional deterioration could be ameliorated by a neural transplant, micrencephalic rats bearing solid transplants of normal fetal neocortical tissue since infancy were evaluated on a visual pattern discrimination learning at 15 months and a spatial navigation test at 24 months of age. The transplant-bearing rats learned both tasks significantly better than the micrencephalic rats without transplants. Morphometric analyses revealed that cortical pyramidal neurons were larger in the transplant-bearing rats than in micrencephalic rats without transplants. The life-long presence of a transplant appeared to have protected the micrencephalic brain against aging-associated deterioration. This is the first demonstration that a neural transplant, placed in a congenitally defective infant brain, can ameliorate aging-associated cognitive deficits.

A new case of Aase-Smith syndrome has been reported with additional findings, including microcephaly, axial rotation of the kidneys, preaxial polydactyly and leukopenia. The patient had almost complete clinical remission with corticosteroid treatment. The findings in this case suggest that it is very difficult to differentiate Aase-Smith syndrome from Blackfan-Diamond and Fanconi's anemias as well as from those cases reported by Murphy and Lubin, and Jones and Thompson.

Sixty-seven appropriate-for-date infants with gestations less than 33 weeks were followed for 12 months after their term dates. All had been born after September 1970. None received hypercaloric alimentation as neonates. Growth from the expected date of delivery was compared with that of 24 normal full-term infants and with accepted growth standards. The boys did not differ from the controls or the standard in mean weight, length, and head circumference, in weight and height indices, or in velocity of weight and linear growth. The girls had a slower velocity of weight growth for the first six months and had significantly lower weight indices at 12 months than did their controls. Velocity of linear growth, height indices, and mean length and head circumference for the girls were similar to those of the control standards. Gross central nervous system defects occurred in 22.5% of the boys but in none of the girls. More than one half of the abnormalities were hydrocephaly. The mean post-conceptional developmental quotient was 110 for the girls and 108 for the boys.