Thrombocytopenia-absent radius (tar) syndrome: a case with agenesis of corpus callosum, hypoplasia of cerebellar vermis and horseshoe kidney

The thrombocytopenia-absent radius (TAR) syndrome (MIM 274000) is a congenital malformation syndrome characterised by bilateral absence of the radii with present thumbs, hypomegakaryocytic thrombocytopenia and a number of additional features including skeletal and cardiac anomalies. Mental retardation, reported in about 7% of patients, is usually secondary to intracranial hemorrhage. In 1994 there was a single report of a girl with TAR syndrome and hypoplasia of the cerebellar vermis and corpus callosum and in 2003 another case of TAR syndrome with cerebellar dysgenesis has been reported. In 2000 there was first report of horseshoe kidney in association with TAR syndrome followed by a clinical study of 34 cases with TAR syndrome in 2002 where horseshoe kidney was noted in two cases. Here we report of a girl with TAR syndrome, severe mental retardation, agenesis of corpus callosum, hypoplasia of cerebellar vermis and horseshoe kidney. There is no previous report of a child with TAR syndrome and all those associated anomalies in the same patient.     

Partial trisomy 7q and monosomy 13q in a child with disorder of sex development: Phenotypic and genotypic findings

Terminal 7q duplication and terminal 13q deletion are two conditions with variable phenotypes including microcephaly, thumb a-/hypoplasia, cortical dysplasia, microphtalmia, intellectual disability and dysmorphic features. We describe a boy born to a mother with a reciprocal t (7;13) who combines both a terminal 7q33-qter duplication and terminal 13q33-qter deletion through the inheritance of a derivative chromosome 13 (der (13)). The patient presented with developmental delay, facial and non-facial dysmorphic features, hypertonia, genital abnormality and skeletal malformation but no thumb a-/hypoplasia or microphtalmia. Knowing the exact breakpoints of his chromosomal aberrations using high resolution array CGH (aCGH) and comparison of his phenotypes with those of 24 and 59 previously published cases of 7q duplication and 13q deletion, respectively, allow us to further narrow the size of the proposed critical regions for microcephaly, thumb a-/hypoplasia and hypo/hypertonia on chromosome 13.     

Ectrodactyly/split hand feet malformation

Split-hand/split-foot malformation is a rare limb malformation with median clefts of the hands and feet and aplasia/hypoplasia of the phalanges, metacarpals and metatarsals. When present as an isolated anomaly, it is usually inherited as an autosomal dominant form. We report a case of autosomal recessive inheritance and discuss the antenatal diagnosis, genetic counseling and treatment for the malformation.     

Mutations in LAMB1 Cause Cobblestone Brain Malformation without Muscular or Ocular Abnormalities

Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation.     

Otocephaly, and pulmonary malformation association: two case reports

Otocephaly is a rare lethal malformation of the first and second branchial arches. We report two infants with otocephaly and failed resuscitation. Both infants had pulmonary malformations: pulmonary hypoplasia and two-lobed right lung. We report these rare associations with a brief review of the literature.     

A new case of partial 14q31.3-qter trisomy due to maternal pericentric inversion

Chromosome 14 is often involved in chromosome rearrangements, although pericentric inversions are rare. Here we report a mother carrying a pericentric inversion of chromosome 14, and her daughter with recombinant chromosome characterized by a partial distal 14q trisomy. Principal clinical findings of the child include facial anomalies, microcephaly, developmental delay, hypotonia and cardiac malformation. Her final karyotype was 46,XX,rec(14)dup(14q)inv(14)(p12q31)mat[20], arr 14q31.3qter(85,427,839–106,356,482)x3. This report brings new data about clinical features of partial 14q trisomy and molecular analysis enables the visualization of genes involved in the segment duplicated.     

Adenoid hypoplasia in the velo-cardio-facial syndrome

The velo-cardio-facial syndrome is one of the most comprehensively studied congenital malformation syndromes of clefting. More than 20 features have been described to date. The purpose of this investigation is to report evidence for congenital hypoplasia of the adenoids in over 80% of the cases studied. Radiographic and nasopharyngoscopic studies of 30 children with velo-cardio-facial syndrome were reviewed along with 30 age- and sex-matched children with nonsyndromic cleft palate to determine the size of their adenoid masses. Eighty-three percent of the subjects with velo-cardio-facial syndrome were found to have small or absent adenoids, whereas only 20% of the controls were found to have small adenoids. None of the control sample had total adenoid absence. These findings may have significant implications for the hypernasal speech patterns often found in individuals with velo-cardio-facial syndrome and may also be related to histories of frequent upper respiratory illnesses in this group.     

Complexities of limb anomalies: the lower extremity in the "prune belly" phenotype

The so-called "prune belly" syndrome (PBS) consists of megalocystis, cryptorchidism, and marked abdominal distension; in addition to these findings, many other abnormalities are commonly present, rarely including severe anomalies of the leg. We report two such individuals, in whom PBS coexisted with abnormal development of the lower extremity. The first, a still-born male fetus, was delivered at 21 weeks gestation; generalized hypoplasia of both legs was present, more marked distally than proximally, and more severe on the left. The second case, a liveborn male infant, was the second of dichorionic twins, delivered at 33 weeks gestation; this infant died at two hours from respiratory insufficiency due to pulmonary hypoplasia. There was severe hypoplasia of the right leg, with gangrenous necrosis of all tissues distal to the knee. Additional findings included a single right umbilical artery, and a small congenital cystic adenomatoid malformation of the right lung. The findings in these cases are compared to other similar cases in the literature, and possible mechanisms for the etiology and pathogenesis of maldevelopment of the leg in PBS are discussed.     

A child with mosaicism for deletion (14)(q11.2q13)

In this case report we describe a child with a de novo deletion in the (q11.2q13) region of chromosome 14. The child presented with dysmorphic features - anophthalmia, microcephaly, and growth retardation. Cytogenetic studies showed mosaicism. The karyotype was 46,XX,del(14)(q11.2;q13) [16] /46,XX [9]. We compared the features observed in this child with that of others with the same deletion reported in scientific literature and found that this is the first report of a child mosaic for this deletion. It is also the first time it has been reported in association with anophthalmia.     

Indications for conservative management of scoliosis (guidelines)

We report a 15-year-old girl who presented with spinal malsegmentation, associated with other skeletal anomalies. The spinal malsegmentation was subsequently discovered to be part of the spondylocarpotarsal synostosis syndrome. In addition, a distinctive craniocervical malformation was identified, which included atlanto-axial rotatory fixation. The clinical and the radiographic findings are described, and we emphasise the importance of computerised tomography to characterize the craniocervical malformation complex. To the best of our knowledge, this is the first clinical report of a child with spondylocarpotarsal synostosis associated with atlanto-axial rotatory fixation.     

Molecular characterization, tissue distribution and expression analysis of interleukin-12 receptor β2 chain in sheep

Agnathia-otocephaly is a rare, often lethal malformation characterized by absence or hypoplasia of the mandible, microstomia, hypoglossia/aglossia, and variable anterior midline fusion of the ears (melotia, synotia). Etiologies have been linked to both genetic and teratogenic factors and to date, a definitive, commonly identifiable cause has not been recognized. Mouse and human genetic studies have implicated OTX2 and PRRX1 as potential candidate genes for agnathia-otocephaly. In this study we report a sporadic case of agnathia-otocephaly complex with associated features of maldevelopment and examine the roles of OTX2 and PRRX1. The proband, a male born at 31 weeks, displayed severe micrognathia, microstomia, posteriorly-rotated and low set ears, and downward slanting palpebral fissures. Mutation analysis was performed after sequencing the entire coding regions of OTX2 and PRRX1 genes isolated from the proband and his parents. After thorough analysis, no DNA variations were detected. This suggests that mutations in different genes or environmental causes are responsible.     

Inferior Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation in Purebred Eurasier Dogs with Familial Non-Progressive Ataxia: A Retrospective and Prospective Clinical Cohort Study

Cerebellar malformations can be inherited or caused by insults during cerebellar development. To date, only sporadic cases of cerebellar malformations have been reported in dogs, and the genetic background has remained obscure. Therefore, this study`s objective was to describe the clinical characteristics, imaging features and pedigree data of a familial cerebellar hypoplasia in purebred Eurasier dogs. A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5 – 6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior) fossa resembled a Dandy-Walker-like malformation in some dogs. Pedigree analyses were consistent with autosomal recessive inheritance.     

Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly

Schizencephaly (SCH) is a clinically and etiologically heterogeneous cerebral malformation presenting as unilateral or bilateral hemispheric cleft with direct connection between the inner and outer liquor spaces. The SCH cleft is usually lined by gray matter, which appears polymicrogyric implying an associated impairment of neuronal migration. The majority of SCH patients are sporadic, but familial SCH has been described. An initial report of heterozygous mutations in the homeobox gene EMX2 could not be confirmed in 52 patients investigated in this study in agreement with two independent SCH patient cohorts published previously. SCH frequently occurs with additional cerebral malformations like hypoplasia or aplasia of the septum pellucidum or optic nerve, suggesting the involvement of genes important for the establishment of midline forebrain structures. We therefore considered holoprosencephaly (HPE)-associated genes as potential SCH candidates and report for the first time heterozygous mutations in SIX3 and SHH in a total of three unrelated patients and one fetus with SCH; one of them without obvious associated malformations of midline forebrain structures. Three of these mutations have previously been reported in independent patients with HPE. SIX3 acts directly upstream of SHH, and the SHH pathway is a key regulator of ventral forebrain patterning. Our data indicate that in a subset of patients SCH may develop as one aspect of a more complex malformation of the ventral forebrain, directly result from mutations in the SHH pathway and hence be considered as yet another feature of the broad phenotypic spectrum of holoprosencephaly.     

Nasal fossa malformations and paramedian facial cleft: new perspectives.

Choanal atresia may be associated with other cranio-facial malformations, including various degrees of nasal fossa malformation, and may be a part of paramedian facial clefts (as described by Tessier et al. [1977]). We identified five such cases with combined clinical elements corresponding to Tessier's paramedian facial cleft, including eyelid coloboma, mild to severe choanal and nasal fossa anomalies, ethmoidal hypoplasia and anterior skull base malformation, sometimes with proboscis lateralis and half-nose hypoplasia. These observations incited us, first, to elaborate a conception which accounts for the likely embryological mechanisms involved; second, to propose a new classification based on anatomical and pathogenic embryological considerations; and last, to propose the use of transpalatal approach to restore choanal permeability, since endonasal laser therapy is particularly dangerous in such cases.     

Pierre-Robin综合征的遗传调控机制

Pierre-Robin综合征（Pierre-Robin syndrome，PRS）是一种能引起颅面器官异常的遗传性疾病，主要表现为下颌发育不全、舌后坠和腭裂等，进而导致新生儿喂食困难，甚至危及个体生命的阻塞性呼吸暂停，是先天性颅面畸形中较为常见的一种综合征。该综合征在全球的发病率为1/8 500~1/14 000，不仅影响个体的生长发育还影响其受教育程度，对患者造成巨大影响，受到社会的广泛关注。虽然Pierre-Robin综合征的临床特征明显，易于诊断，但不同患者间高相似性的表型很容易掩盖患病个体之间的病理学异质性，从而很难确定每例Pierre-Robin综合征的具体病因。因此，了解Pierre-Robin综合征的发病原理及其遗传机制，对于防治Pierre-Robin综合征尤为重要。由基于此，本文结合新近几年在Pierre-Robin综合征发病机制方面的相关研究，主要对引起该综合征的关键信号通路及其相关分子机制，特别是不同信号通路间的相互作用机制进行综述，从而进一步理解Pierre-Robin综合征发生的遗传调控机制。     

Renal tubular dysgenesis with hypoplastic calvaria: report of two cases

Renal tubular dysgenesis (RTD), a rare, lethal, autosomal recessive disorder, is characterized by short and poorly differentiated proximal tubules and associated with hypoplastic calvaria. We report two cases of RTD with hypoplasia of the calvaria. Microscopically, proximal tubules in the kidneys were not seen on routine H&E stain. Almost all tubules in the cortex were stained for epithelial membrane antigen (EMA), confirming the absence of proximal tubule differentiation. The autopsy findings, microscopic features and the etiology of this rare condition is discussed and compared with literature data.     

Congenital hemicerebral anomaly in a stranded Pacific harbor seal (Phoca vitulina richardsi)

A stranded 5-month-old female Pacific harbor seal (Phoca vitulina richardsi) was presented displaying tachypnea and diminished lung sounds. No neurological abnormalities were noted. The animal was treated for verminous pneumonia, but died 2 wk later. Gross necropsy examination revealed a severe obstructive verminous pneumonia associated with large numbers of Otostrongylus circumlitus. In addition, the majority of the right cerebral hemisphere was absent, with hypoplasia of the left cerebellar hemisphere, absence of the right pyramid, and malformation of the right occipital bone. Histopathologic findings included multifocal thrombosis and inflammation of pulmonary arteries, verminous pneumonia, and mild vacuolation of the subependymal white matter in the third ventricle representing swelling of myelin sheaths and edema. This is the first report of a hemicerebral anomaly in a marine mammal.     

Coexistance of cerebral sinovenous thrombosis and Dandy Walker malformation in newborn

Cerebral sinovenous thrombosis in neonatal period may cause neurological impairment, epilepsy, and lead to stroke. It is caused primarily by coagulopathy of numerous reasons, occasionally perinatal asphyxia, traumatic delivery and hyperhomocysteinemia. Dandy-Walker malformation is characterized by agenesis or hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle, and enlargement of the posterior fossa. Dandy-Walker malformation, variant, and mega cisterna magna represent a spectrum of developmental anomalies. Insults to developing cerebellar hemispheres and the fourth ventricle are believed to be the cause of malformation. Our patient was born from noncomplicated pregnancy, noncomplicated nontraumatic vaginal delivery at term, excellent Apgar scores, without peculiarities in clinical status. She was brest-fed by the 42nd hour of life when she had rightsided seizures during sleep that repeated for five times in next 24 hours. Brain Ultrasound (US) revealed clot in left lateral ventricle, slight dilatation of left ventricle, both sided periventricular echodensity, ischemia, slight enlargement of forth ventricle and a bit smaller cerebellum. There was no visible flow through left transverse, superior sagittal and straight sinus. Magnetic Resonance (MRI) confirmed the finding and showed thrombosis of left and right transverse venous sinuses and confluence of sinuses. Electroencephalogram (EEG) showed leftsided focal changes. The newborn was treated with phenobarbiton for 8 days and had no convulsions during that period. All coagulation parameters, homocistein, lipoproteins (a) and D-dimers were normal. There were no mutations on FV R506Q, PT 20210A, MTHFR 677C/T. No antiphospholipides were found. Heart US showed no structural anomalies. No other patology or risk factors were present at the time. Before discharge, US showed hydrocephalus. Flow in affected sinuses was visible with color Doppler. MRI showed recanalization of affected sinuses, also hydrocephalus and presentation of Dandy Walker On EEG there was borderline finding. Due to progression of hydrocephalus ventriculo-peritoneal shunt was placed. In age of 1 year EEG was slower for age but without focus. Neurological development was normal for age. The question is whether this child had intrauterine insult and inception of Dandy Walker with further postnatal progress of thrombosis and evolution to full picture of Dandy Walker with hydrocephalus OR thrombosis that led to development of hydrocephalus and Dandy Walker malformation in this child were accidental coexistance.