Search

CHARGE association describes a group of birth defects characterized by eye and heart defects, airway and esophagus abnormalities, retardation, small genitals, and ear and hearing defects. Children born with this condition will often have several defects which typify CHARGE, an acronym for the key disorders. The heart, respiratory and esophageal abnormalities may necessitate surgery to improve heart function, eating, and breathing. CHARGE patients will often have delayed and impaired motor and mental development. The condition appears to result from genetic mutation.

Infants and children with chromosome 22q11 deletion syndrome may exhibit various symptoms and abnormalities. Chromosome 22q11 deletion syndrome may be inherited or result from a genetic mutation, and may be detected with fluorescent in situ hybridization (FISH). Other diagnostic tests include high-resolution chromosome analysis, thyroid function testing, and blood calcium measurements. Characteristic diagnostic features include developmental abnormalities of the heart, clefting of the posterior palate, malformed facial features, and long, tapered fingers. Infants may experience nasal regurgitation, poor growth, and lack of muscle tone. Learning disabilities are universal. Early detection and intervention are important.

Children born with mildly malformed ears may not need surgery to reshape ears but reshaping should be done in the newborn period. Reshaping can be accomplished by taping the ear with cotton to hold the ear in the desired shape. More severely deformed ears usually require surgery. Infants born with very small ears need to wait until they are about six years old for surgery, when their ribs can be used as ear cartilage to reconstruct ears. In the meantime, these infants need hearing aids by age three months.

The primary care physician should be able to diagnose and treat Beckwith-Wiedemann syndrome because prognosis is generally good. Unrecognized, it can pose several life-threatening complications. Beckwirth-Wiedemann syndrome, also called EMG-syndrome, is a rare, inheritable disease characterized by an overly large infant, overgrowth and abnormalities of abdominal organs, defects of the abdominal wall muscles, an enlarged tongue, and certain distinctive facial features. Serious complications include low blood sugar in the newborn, a predisposition to form certain tumors such as Wilms tumor, which is a kidney tumor, and difficulties breathing or feeding due to the overly large tongue. With proper screening and treatment, most children will grow into normal-appearing adults of normal intelligence and normal sexual development.

Rett syndrome is a common developmental-neurologic disorder reported in females almost exclusively. Recently, the ability to recognize this condition has improved. As a result, clarifying the management of this disorder for affected individuals has been expedited. For the family of a girl with Rett syndrome, the primary care physician can become a significant source of support and advocacy. Numerous resources available to the primary care giver and the families of children with Rett syndrome are listed; these may be useful in obtaining early diagnosis, psychological support and preventive medical care. Future requirements for patients and care givers are described. The current state of knowledge regarding Rett syndrome is reviewed and a framework provided for medical and developmental interventions.

Down syndrome (DS), which was first described in 1865, is characterized by the genetic variant known as trisomy 21; the presence of three, instead of two, number 21 chromosomes. This condition occurs in all cultures, ethnic groups, socioeconomic groups, and geographic areas. The constellation of clinical features of DS includes generally diminished muscle tone, flattened midface and depressed nasal bridge, upward angle of the outer eyelid, shortened fingers, congenital heart defects, ocular (eye) defects, hearing defects, bowel defects, premature senescence (aging), and diminished mental development. Today patients with DS have prospects of a healthier, more productive, and more fulfilling life than DS patients born as recently as 1965, when 50 percent of affected children died before their fifth birthday. Instead of being placed in institutions, DS patients are now more likely to be kept at home and nurtured by their families. They have greater access to health care and treatment innovations, and there is greater community involvement in providing them with opportunities for mainstreaming, education, and employment. Details of early diagnosis, and approaches to advising and helping families through the initial shock of being informed that their child has Down syndrome are discussed. Growth charts for boys and girls with DS are included, and health problems and management techniques are presented in detail according to the organ systems involved. Lists of resources for further information are provided for physicians and the parents of children with DS. (Consumer Summary produced by Reliance Medical Information, Inc.)

This introduction to the special issue of AJMG Part C: Overgrowth Syndromes updates the current understanding of overgrowth syndromes. We clarify the terminology associated with overgrowth, review some common pathways to overgrowth and present a preliminary classification based on currently known genomic and epigenetic mechanisms. We introduce the articles of this issue—new research and reviews of well‐established and recently described overgrowth syndromes of the brain, body or both.

The nucleosome remodeling and deacetylase (NuRD) complex is a major regulator of gene expression involved in pluripotency, lineage commitment, and corticogenesis. This important complex is composed of seven different proteins, with mutations in CHD3, CHD4, and GATAD2Bbeing associated with neurodevelopmental disorders presenting with macrocephaly and intellectual disability similar to other overgrowth and intellectual disability (OGID) syndromes. Pathogenic variants in CHD3and CHD4primarily involve disruption of enzymatic function. GATAD2Bvariants include loss‐of‐function mutations that alter protein dosage and missense variants that involve either of two conserved domains (CR1 and CR2) known to interact with other NuRD proteins. In addition to macrocephaly and intellectual disability, CHD3variants are associated with inguinal hernias and apraxia of speech; whereas CHD4variants are associated with skeletal anomalies, deafness, and cardiac defects. GATAD2B‐associated neurodevelopmental disorder (GAND) has phenotypic overlap with both of these disorders. Of note, structural models of NuRD indicate that CHD3 and CHD4 require direct contact with the GATAD2B‐CR2 domain to interact with the rest of the complex. Therefore, the phenotypic overlaps of CHD3‐ and CHD4‐related disorders with GAND are consistent with a loss in the ability of GATAD2B to recruit CHD3 or CHD4 to the complex. The shared features of these neurodevelopmental disorders may represent a new class of OGID syndrome: the NuRDopathies.

CHD8has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p< .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.

PURPOSE: To demonstrate favorable long-term visual outcome after ocular reconstruction in an infant with Fraser syndrome and with complete left cryptophthalmos. METHODS: Reconstruction of incomplete right cryptophthalmos in our patient was accomplished in a stepwise manner, beginning in the third week of life, by dissecting the eyelids from the cornea, reconstructing the conjunctival fornices with buccal mucosa, and repairing the upper lid coloboma in a flap reconstruction using the inferior eyelid margin. RESULTS: At age 3 years, the patient currently has good movement of the right eyelids when blinking, reasonable right tear function, and a visual acuity in the right eye between 20/200 and 20/360 on forced preferential looking. CONCLUSION: In selected cases of incomplete cryptophthalmos, oculoplastic and corneal surgery may result in useful vision and in good eyelid movement when blinking.

To investigate the effect of different DEAF1variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro.

To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients.

Cedars-Sinai Grand Rounds Series Editor: Alan T. Lefor, MD, MPH Case Report S.Q. was 4 months old when she came to us from the Gaza Strip. She was born full [...]

The authors discuss neurofibromatosis, also called von Recklinghausen's disease, a genetic disease which is familiar to many primary care physicians but is often not diagnosed in children. They explain symptoms and signs to help pediatricians recognize and provide care for this disease.

N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1mutations (c.1858 G>A and c.1858 G>C; both p.G620R). Both individuals presented at birth with developmental delay and hypotonia associated with behavioral abnormalities and stereotypical movements. Recombinant NMDARs containing the mutant GluN1-G620R together with either GluN2A or GluN2B were evaluated for changes in their trafficking to the plasma membrane and their electrophysiological properties. GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg2+block, and a significant reduction of current responses to a maximal effective concentration of agonists. GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface associated with similarly altered electrophysiology. These results indicate these individuals may have suffered neurodevelopmental deficits as a result of the decreased presence of GluN1-G620R/GluN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of GluN1-G620R-containing NMDARs after birth. These cases emphasize the importance of comprehensive functional characterization of de novomutations and illustrates how a combination of several distinct features of NMDAR expression, trafficking and function can be present and influence phenotype.

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Several letters to the editor are presented in response to articles in previous issues including "How Do You Doctor an Ailing Railroad?" in the January 3, 1953 issue, "Bolstering Up Morale" in the December 13, 1952 issue, and "Where Do Trucks Go From Here?" in the November 22, 1952 issue.

Williams-Beuren syndrome is a genetic disorder that causes mental retardation, heart defects, characteristic changes in the face, and sometimes increased calcium in the blood.

The pontocerebellar hypoplasias PCH are a group of earlyonset, autosomal recessive disorders resulting in abnormal growth and function of the brainstem and cerebellum. PCH type 2 PCH2 is characterized by respiratory and feeding difficulties at birth, extrapyramidal dyskinesia, severe developmental impairment, progressive microcephaly and frequent death in childhood. Neuropathologic findings include diffuse cerebral gliosis with white matter changes, hypoplastic pons with depletion of neurons in the pontine nuclei, hypoplastic cerebellar hemispheres due to short cerebellar folia with poor branching, segmental loss of dentate, inferior olivary, and ventral pontine nuclei, and near absence of transverse pontine fibers with preservation of long fiber tracts and spinal anterior horn cells. On brain imaging, the cerebellar hemispheres appear very flat, and are more severely involved than the vermis. Most patients with PCH2 have mutations in TSEN54, with occasional mutations found in TSEN34or TSEN2, genes that encode subunits of tRNA splicing endonuclease. Although this is a congenital disorder of pontocerebellar dysgenesis with fetal onset of neurodegeneration and symptoms at birth, prenatal imaging is unreliable in diagnosing this disorder in utero. We report on IVF dizygous twins with detailed prenatal imaging that failed to reveal any cerebellar abnormalities. Direct sequence analysis of TSEN54showed homozygosity for c.919G>T, the common founder mutation in most PCH2 patients, and both parents were heterozygous for this mutation. We found no evidence of cerebellar dysgenesis on prenatal ultrasounds, but MRI tractography showed absence of pontine crossing fibers, a unique feature that might be useful for prenatal diagnosis of this condition. © 2010 WileyLiss, Inc.

Nonsyndromic craniosynostosis is multifactorial, and fetal head constraint has been hypothesized as one factor thought to play a role. Data from the National Birth Defects Prevention Study NBDPS, a large multisite case–control study of birth defects, were used to evaluate associations between four selected factors related to fetal constraint and craniosynostosis: plurality twins or higher, macrosomia birth weight >4,000 g, postterm gestational age ≥42 weeks, and nulliparity no previous live births. Case infants n  675 had craniosynostosis documented either by radiographic evidence or by surgical intervention. Infants with a recognized or strongly suspected singlegene conditions or chromosomal abnormalities were excluded. Control infants n  5,958 had no major birth defects and were randomly selected from the same population as case infants. Logistic regression was used to estimate odds ratios for the association between these four factors and craniosynostosis, while adjusting for several covariates. We found that plurality and nulliparity were associated with a twofold increased risk for metopic craniosynostosis, and macrosomia had almost twice the risk of developing coronal craniosynostosis. Contrary to our hypothesis, prematurity and low birth weight were also associated with craniosynostosis. In conclusion, these four constraintrelated factors were not found to be associated with craniosynostosis when all suture types were combined, though some types of craniosynostosis were associated with individual constraintrelated factors. © 2010 WileyLiss, Inc.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia due to mutations causing haploinsufficiency of RUNX2, an osteoblast transcription factor specific for bone and cartilage. The classic form of CCD is characterized by delayed closure of the fontanels, hypoplastic or aplastic clavicles and dental anomalies. Clinical reports suggest that a subset of patients with CCD have skeletal changes which mimic hypophosphatasia (HPP). Mutations in RUNX2are detected in approximately 65% of cases of CCD, and microdeletions occur in 13%. We present clinical and radiological features in a 6‐year‐old child with severe CCD manifested by absence of the clavicles marked calvarial hypomineralization, osteoporosis and progressive kyphoscoliosis. HPP features included Bowdler spurs, severe osteopenia, and low alkaline phosphatase. Following negative mutation analysis of RUNX2, comparative genomic hybridization (CGH) microarray was performed. The result revealed a microdeletion in RUNX2, disrupting the C‐terminal part of the gene. © 2009 Wiley‐Liss, Inc.

Abstract: FG syndrome is a rare X-linked multiple congenital anomaly-cognitive impairment disorder caused by the p.R961W mutation in the MED12 gene. We identified all known patients with this mutation to delineate their clinical phenotype and devise a clinical algorithm to facilitate molecular diagnosis. We ascertained 23 males with the p.R961W mutation in MED12 from 9 previously reported FG syndrome families and 1 new family. Six patients are reviewed in detail. These 23 patients were compared with 48 MED12 mutation-negative patients, who had the clinical diagnosis of FG syndrome. Traits that best discriminated between these two groups were chosen to develop an algorithm with high sensitivity and specificity for the p.R961W MED12 mutation. FG syndrome has a recognizable dysmorphic phenotype with a high incidence of congenital anomalies. A family history of X-linked mental retardation, deceased male infants, and/or multiple fetal losses was documented in all families. The algorithm identifies the p.R961W MED12 mutation-positive group with 100% sensitivity and 90% specificity. The clinical phenotype of FG syndrome defines a recognizable pattern of X-linked multiple congenital anomalies and cognitive impairment. This algorithm can assist the clinician in selecting the patients for testing who are most likely to have the recurrent p.R961W MED12 mutation.

Noonan syndrome NS is a genetically heterogeneous disorder caused most commonly by activating mutations in PTPN11. We report a patient with hypotonia, developmental delay and clinical features suggestive of NS. Highresolution chromosome analysis was normal, and sequence analyses of PTPN11, SOS1, KRAS, BRAF, RAF1, MEK, and MEK2were also normal. Array CGH revealed a single copy gain of 9 BAC clones at 12q24.11q24.21 8.98 Mb in size, which encompassed the PTPN11locus at 12q24.13 and was confirmed by FISH analysis. Shchelochkov et al. Shchelochkov et al. 2008; Am J Med Genet Part A 146A:1042–1048 reported a similar case and speculated that such duplications might account for 15–30 of NS cases with no detectable mutation in NS genes. We screened more than 250 NS cases without mutation in known NS diseasecausing genes by quantitative PCR, and none of these studies produced results in the duplicated range. We also explored the possibility that de novo changes affecting the untranslated region UTR of the PTPN11transcript might represent an alternative event involved in SHP2 enhanced expression. DHPLC analysis and direct sequencing of the entire 3′ UTR in 36 NS patients without mutation in known genes did not show any diseaseassociated variant. These findings indicate that duplications of PTPN11represent an uncommon cause of NS, and functionally relevant variations within the 3′UTR of the gene do not appear to play a major role in NS. However, recurrent observations of NS in individuals with duplications involving the PTPN11locus suggest that increased dosage of SHP2 may have dysregulating effects on intracellular signaling. © 2009 WileyLiss, Inc.

BACKGROUND: Diabetes is the most common endocrinologic complication during pregnancy, and poor control can lead to a variety of congenital anomalies in the fetus. However, it is often difficult to differentiate between diabetesrelated anomalies and an underlying genetic syndrome. In the 1990s it was proposed that preaxial hallucal polydactyly, particularly when proximally placed, was a distinguishing feature of diabetic embryopathy. METHODS: We summarize the clinical findings in 18 patients five previously reported in abstract form with diabetic embryopathy and preaxial hallucal polydactyly to determine which features are most suggestive of diabetic embryopathy. RESULTS: All 18 patients had preaxial hallucal polydactyly seven bilateral, 11 unilateral, of which 15 patients had proximal implantation of the extra hallux. Further skeletal findings included the following: segmentation anomalies of the spine, equinovarus deformity of the feet, tibial hemimelia, hip dysplasia, and femoral hypoplasia. Upper limb malformations were rare. Eleven of the 18 mothers had prepregnancy insulindependent diabetes, while one mother had prepregnancy type 2 diabetes that required insulin therapy in the 3rdtrimester. Five mothers had gestational diabetes that required insulin and one mother had gestational diabetes that was controlled by diet. The majority of mothers had poorly controlled diabetes during the pregnancy. CONCLUSIONS: Proximally placed preaxial hallucal polydactyly, particularly when coupled with segmentation anomalies of the spine and tibial hemimelia, is highly suggestive of diabetic embryopathy. Varying degrees of diabetes in the mothers point to a possible genetic predisposition interacting with the teratogenic effects of poor glycemic control leading to specific limb anomalies. Birth Defects Research Part A, 2009. © 2008 WileyLiss, Inc.

An international group of clinicians working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we introduce the anatomy of the periorbital area and define and illustrate the terms that describe the major characteristics of the periorbital area. © 2009 WileyLiss, Inc.

Opitz and Kaveggia Opitz and Kaveggia 1974; Z Kinderheilk 117:1–18 reported on a family of five affected males with distinctive facial appearance, mental retardation, macrocephaly, imperforate anus and hypotonia. Risheg et al. Risheg et al. 2007; Nat Genet 39:451–453 identified an identical mutation p.R961W in MED12in six families with Opitz–Kaveggia syndrome, including a surviving affected man from the family reported in 1974. The previously defined behavior phenotype of hyperactivity, affability, and excessive talkativeness is very frequent in young boys with this mutation, along with socially oriented, attentionseeking behaviors. We present case studies of two older males with FG syndrome and the p.R961W mutation to illustrate how their behavior changes with age. We also characterize the behavior of eight additional individuals with FG syndrome and this recurrent mutation in MED12using the Vineland Adaptive Behavior Scales 2nd edition, the Reiss Profile of Fundamental Goals and Motivation Sensitivities, and the Achenbach Child Behavior Checklist. Males with this MED12mutation had deficits in communication skills compared to their socialization and daily living skills. In addition, they were at increased risk for maladaptive behavior, with a propensity towards aggression, anxiety, and inattention. Based on the behavior phenotype in 10 males with this recurrent MED12mutation, we offer specific recommendations and interventional strategies. Our findings reinforce the importance of testing for the p.R961W MED12mutation in males who are suspected of having developmental and behavioral problems with a clinical phenotype that is consistent with FG syndrome. © 2008 WileyLiss, Inc.

Useful and meaningful counseling following the discovery of a fetal loss or fetal anomalies requires an accurate diagnosis. In order to achieve this, our center utilized a multidisciplinary approach which included an ultrasonographer, perinatologist, genetic counselor, dysmorphologist, clinical geneticist, and pathologist. In this article, we report our experience with the analysis and evaluation of 534 cases seen between 1989 and 2000. In total, we were able to identify the cause of fetal loss in 369 cases (69%). In 98/369 cases (18.4%) the condition was attributed to a Mendelian process and in 78 (14.6%), to chromosomal abnormalities. The overall average maternal age was 31.6 years, the maternal age in cases of chromosomal abnormality was slightly higher (33.3 years). Our findings described below reiterate the clinical usefulness of a team specifically trained in the approach to fetal loss and/or fetal anomalies. © 2007 Wiley‐Liss, Inc.

Wormian bones are accessory bones that occur within cranial suture and fontanelles, most commonly within the posterior sutures. They occur more frequently in disorders that have reduced cranial ossification, hypotonia or decreased movement, thereby resulting in deformational brachycephaly. The frequency and location of wormian bones varies with the type and severity of cranial deformation practiced by ancient cultures. We considered the hypothesis that the pathogenesis of wormian bones may be due to environmental variations in dural strain within open sutures and fontanelles. In order to explore this further, we measured the cephalic index (CI) in 20 purposefully deformed pre‐Columbian skulls: 10 from Chichen Itza, Mexico, and 10 from Ancon, Peru, as well as 20 anatomically normal skulls used for medical school anatomy classes. We tested for a direct correlation between the CI and the number of wormian bones in skulls with varying degrees of brachycephalic cranial deformation and found no significant correlation. When the CI was grouped into three categories (normal (CI < 81), brachycephalic (CI 81‐93), and severely brachycephalic (CI > 93)) there was a trend toward increasing number of wormian bones as the skull became more brachycephalic (P = 0.039). A second part or our study tabulated the frequency and location of large wormian bones (greater than 1 cm) in 3‐dimentional computerized tomography (3D‐CT) scans from 207 cases of craniosynostosis and compared these data with published data on 485 normal dry skulls from a manuscript on wormian bones by Parker in 1905. Among cases of craniosynostosis, large wormian bones were significantly more frequent (117 out of 207 3D‐CT scans) than in dry skulls (131 out of 485). There was a 3.5 greater odds of developing a wormian bone with premature suture closure (P < 0.001). Midline synostosis, specifically metopic or sagittal synostosis, has more wormian bones in the midline, whereas unilateral lambdoidal or coronal synostosis more often had wormian bones on the contralateral side. Taken together, these data suggest that wormian bones may arise as a consequence of mechanical factors that spread sutures apart and affect dural strain within sutures and fontanelles. © 2007 Wiley‐Liss, Inc.

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly–Capillary Malformation (M–CM). This syndrome has been traditionally known as Macrocephaly–Cutis Marmorata Telangiectatica Congenita (M–CMTC), but we explain why M–CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2‐weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow–Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M–CM. © 2007 Wiley‐Liss, Inc.

We report on six cases from four families with the newly described skeletal disorder diaphanospondylodysostosis (DSD). The characteristic radiographic findings included abnormal ossification of vertebral bodies, posterior rib gaps, missing ribs, and a downward tilt of the pubic rami, but normal long bones. The typical facial features of DSD cases were ocular hypertelorism, a short nose, depressed nasal bridge, and low set ears. Other distinctive findings included a short neck with bell‐shaped thorax, and nephroblastomatosis. A history of consanguinity and affected siblings with unaffected parents supports autosomal recessive inheritance. Skeletal histology showed incomplete ossification of the ribs, vertebral bodies, and sacrum as well as incomplete formation of intervertebral discs. The posterior ribs were comprised of bone with intervening cartilage interrupted by dense fibrous tissue and skeletal muscle fascicles. These findings suggest abnormal development and differentiation of the paraxial mesoderm. Because of phenotypic similarities of DSD to Pax1 and Meox1 deficient mice, we sequenced genomic DNA from three unrelated DSD cases. No mutations were identified in the PAX1 and MEOX1 exons or flanking intronic sequences, excluding them as likely causative genes. © 2007 Wiley‐Liss, Inc.

Sex chromosomal aneuploidy is the most common disorder of sex chromosomes in humans, with an incidence of 1 in 400 newborns. The addition of more than one extra X and/or Y chromosome to a normal male karyotype is less frequent and has its own distinctive physical and behavioral profile. This study examines the behavioral similarities and differences in individuals with 48,XXYY compared to 48,XXXY and 49,XXXXY. The participants include 11 males with 48,XXYY and 13 males with 48,XXXY and 49,XXXXY. Using the Vineland Adaptive Behavior, the Achenbach Child Behavior Checklist, and the Reiss Personality Profiles, parents are asked to characterize the behavior and personality of their boys with sex chromosome tetrasomy and pentasomy. Males with 48,XXYY have higher overall adaptive scales in daily living skills, socialization, and communication compared to males with 48,XXXY and 49,XXXXY. Both groups are at risk for maladaptive behavior, although 48,XXYY males are at a higher risk for internalizing and externalizing symptoms. 48,XXXY and 49,XXXXY function at a lower cognitive level and their behavior is often immature for their chronological age. Both groups display interests in helping others, but have a low tolerance for being rejected or teased. Specific recommendations and interventional strategies are provided for individuals with 48,XXYY, 48,XXXY, and 49,XXXXY. © 2007 Wiley‐Liss, Inc.

Currarino syndrome consists of autosomal dominant hereditary sacral dysgenesis that is caused by mutations of the HOX gene, HLXB9. Sacral malformation, presacral mass, and anorectal malformations comprise the classic triad, but other common symptoms and malformations include neonatal‐onset bowel obstruction, chronic constipation, recurrent perianal sepsis, renal/urinary tract anomalies, female internal genital anomalies, tethered spinal cord, and anterior meningocele. Up to 33% of patients are asymptomatic. There is marked inter‐ and intrafamilial variability in expression, and no genotype/phenotype correlations have been identified. To date, 32 different mutations have been identified in HLXB9: all nine missense mutations were found in the homeodomain, while the others were nonsense, frameshift, splice site mutations, or heterozygous whole‐gene deletions. We report a four‐generation family with Currarino syndrome varying in severity from very mild to full expression of the Currarino triad. They were found to carry a previously unreported nonsense mutation, E283X, absent in tested asymptomatic first‐degree relatives. This family provides additional information on the degree of intrafamilial variability associated with HLXB9 mutations. © 2006 Wiley‐Liss, Inc.

Abstract:This research note examines the Chinese standards system, including its management system and institutions, and the procedures for the development of national standards. In addition, China's technical standards development strategy is covered at length, including its overall goals and methods of implementation.

Bosma et al. [1981] delineated a syndrome affecting two unrelated males with severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence. Other patients with this syndrome have been reported as cases of arhinia with associated defects. During embryonic development, the nasal placodes form 28 days after conception shortly after the optic vesicles makes contact with the overlying surface ectoderm at 26–27 days, and both layers invaginate to form the eyes between 34 and 44 days. Mice with homozygous mutations of Pax6, manifest underdevelopment of ocular and nasal structures, and a network of developmentally regulated genes function downstream of Pax6 to form nasal, ocular, and pituitary structures. These genes represent candidate genes for this disorder, and familial recurrence of Bosma syndrome has been reported to occur. This report describes two sporadic unrelated cases of this rare syndrome and briefly reviews the findings in previously reported cases. © 2005 Wiley‐Liss, Inc.

CHARGE syndrome was independently reported by Hall [(1979): J Pediatr 95:395–398] and Hittner et al. [(1979): J Pediatr Ophthalmol Strabismus 16:122–128] and was initially considered to be a non‐random association between distinct multiple congenital anomalies. It is now considered to be a recognizable syndrome with well‐characterized diagnostic criteria and a genetic pathogenesis. We report on a 33‐year‐old adult male with CHARGE syndrome, with emphasis on the unique medical, behavioral, and psychological issues faced in adulthood. Characteristic facial and ear abnormalities were obvious in early childhood, and bilateral retinal colobomata, left choanal atresia, right congenital hip dislocation, and hypogonadism were diagnosed during the first year. Walking was delayed due to vestibular problems, speech was impaired due to moderately severe hearing loss, and use of sign communication was limited. Choanal atresia was surgically corrected in infancy, and atrial septal defect, ventricular septal defect, and patent ductus arteriosus were surgically corrected in childhood. Undescended testes were removed in adolescence, and gallstones were removed in early adulthood. Puberty was delayed until hormone replacement therapy began at 15 years. Behavioral disturbances and anxiety persisted throughout childhood, adolescence, and into adulthood, often resulting from communication challenges. At 33 years of age, he lives independently in a supervised group home, receives regular eye check‐ups and is being monitored for severely reduced bone density. © 2005 Wiley‐Liss, Inc.

CHARGE syndrome is a well‐characterized clinical diagnosis with recent data supporting a genetic etiology. A 3‐year national surveillance coordinated by the Canadian Pediatric Surveillance Program (CPSP) was started in September 2001. Physicians notified the CPSP if they had cared for individuals with CHARGE syndrome within their practice, and then completed a detailed reporting form. To date, there are 77 confirmed cases of CHARGE syndrome. The highest provincial prevalence of CHARGE syndrome in Canada was estimated at 1 in 8,500 live births. Subgroups of cases with particular clusters of anomalies were identified. In older individuals, bilateral posterior choanal atresia (BPCA) was predictive of the presence of the three other major criteria and of aortic arch anomalies. Individuals with CHARGE syndrome who demonstrated a less extensive phenotype (≤3 major criteria) were more likely to present with minor cardiovascular malformations, including small atrial or ventricular septal defects (VSD) or patent ductus arteriosus (PDA). A significant cause of morbidity was severe feeding difficulty, including problems with chewing, swallowing, and gastroesophageal reflux, which were prevalent throughout childhood. Infant mortality is high in individuals with CHARGE syndrome. However, life expectancy has improved for those surviving their first year. Increased mortality was associated with distinct cardiovascular malformations or ventriculomegaly combined with brainstem or cerebellar anomalies. From this study, revised diagnostic criteria are proposed for infants, children, and adolescents to help identify a group of individuals who represent CHARGE syndrome with more of the classical features as apposed to the boarder association. © 2005 Wiley‐Liss, Inc.

CHARGE syndrome, or Hall–Hitner syndrome (HHS), has been delineated as a common syndrome that includes coloboma, choanal atresia, cranial nerve dysfunction (particularly asymmetric facial palsy and neurogenic swallowing problems), characteristic ear abnormalities, deafness with hypoplasia of the cochlea and semicircular canals, genital hypoplasia, and variable heart defects, orofacial clefting, tracheo‐esophageal fistula, renal anomalies, thymic/parathyroid hypoplasia, spine anomalies, short broad neck with sloping shoulders, and characteristic facial features. We conducted behavioral and personality assessments in 14 boys with HHS syndrome aged 6–21 years, and compared their characteristics with similar data from 20 age‐matched boys with Down syndrome (DS), 17 boys with Prader–Willi syndrome (PWS), and 16 boys with Williams syndrome (WS). We used the Reiss Profile of Fundamental Goals and Motivation Sensitivities, the Achenbach Child Behavior Checklist (CBCL), and the Aberrant Behavior Checklist (ABC). All 14 boys with HHS were legally deaf, and 10 of the 14 were also legally blind. In comparison these other syndromes, boys with HHS had behavior that resembled autistic spectrum disorder. They were socially withdrawn, lacked interest in social contact, and manifested reduced seeking of attention from others, with hyperactivity and a need to maintain order. Though the boys with HHS showed decreased social interaction, they were not as socially impaired as in classic autism. Their language was delayed due to dual sensory impairment, cranial nerve deficits, and chronic medical problems, but their language style was not abnormal (no echolalia or jargon, no scripted phrases, and no pronoun reversal). Boys with HSS appeared frustrated, but they were not aggressive, or at risk for delinquency, manifesting few stereotypic behaviors or unusual preoccupations. They did not have a restricted repertoire of activities and interests. Their behavioral features appeared to be due to dual sensory impairment affecting hearing and vision, rather than to primary autistic spectrum disorder, but successful remediation requires similar educational interventions, which are discussed herein. © 2005 Wiley‐Liss, Inc.

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases—providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined. © 2004 Wiley‐Liss, Inc.

To describe clinical and behavioral features of 10 men from 2 families with Borjeson-Forssman-Lehmann syndrome (BFLS) and missense mutations in the PHF6zinc-finger transcription factor gene.

Children born with the findings of microcephaly, cataracts and microcornea can result not only from a prenatal viral infection, but also from an autosomal recessive Mendelian disorders. We present three pairs of affected siblings with MICRO syndrome, who were born with congenital microcephaly, microcornea, and cataracts. MICRO syndrome is an autosomal recessive syndrome consisting of congenital microcephaly, cortical dysplasia, microcornea, cataracts, optic atrophy, severe mental retardation, hypotonic diplegia, and hypogenitalism. At birth, MICRO syndrome resembles Cerebro‐Oculo‐Facio‐Skeletal (COFS) syndrome, but it differs in the lack of the rapidly progressive neurologic features leading to severe brain atrophy with calcifications. Patients with MICRO syndrome manifest frontal cortical dysplasia, hypoplasia of the corpus callosum, cortical blindness with optic atrophy, profound mental retardation, and progressive joint contractures with growth failure. COFS syndrome shares also many clinical and cellular similarities with Cockayne syndrome (CS), and cultured cells in both conditions demonstrate hypersensitivity to ultraviolet (UV) radiation due to impaired nucleotide excision repair (NER). NER studies in cultured fibroblasts from MICRO patients give normal results, so MICRO syndrome should be considered in children with features resembling COFS syndrome and CS, but who have normal NER. MICRO should be distinguished from other similar clinical disorders with normal NER by the presence of significant visual impairment and cortical blindness despite early surgery for congenital cataracts, frontal polymicrogyria, thin corpus callosum, and cortical atrophy by MRI. © 2004 Wiley‐Liss, Inc.

No abstract

Purpose The purpose of this study is to summarize new data on etiology and clinical features of Klinefelter syndrome in order to derive research priorities.Methods This study was conducted using critical reviews of selective topics, emphasizing less well-recognized clinical findings.Results And Conclusions The phenotype of the prototypic 47,XXY case is well recognized: seminiferous tubule dysgenesis and androgen deficiency. Less well appreciated is the varied expressivity of 47,XXY Klinefelter syndrome, in particular neurological/cognitive perturbations like language and behavioral problems. Effective therapies are available. Reproductive technologies allow 47,XXY men to sire offspring through intracytoplasmic sperm injection (ICSI); however, genetic counseling is complex and success is low. Behavioral and expressive language difficulties are amenable to treatment by androgen therapy and psychological help. Early treatment may be imperative for optimal outcome.