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Objective: Numerous pathogenic variants in KCNB1, which encodes the voltage-gated potassium channel, KV2.1, are linked to developmental and epileptic encephalopathies and associated with loss-of-function, -regulation, and -expression of the channel. Here we describe a novel de novo variant (P17T) occurring in the KV2.1 channel that is associated with a gain-of-function (GoF), with altered steady-state inactivation and reduced sensitivity to the selective toxin, guanxitoxin-1E and is clinically associated with neurodevelopmental disorders, without seizures. Methods: The autosomal dominant variant was identified using whole exome sequencing (WES). The functional effects of the KCNB1 variant on the encoded KV2.1 channel were investigated using whole-cell patch-clamp recordings. Results: We identified a de novo missense variant in the coding region of the KCNB1 gene, c.49C>A which encodes a p.P17T mutation in the N-terminus of the voltage-gated, KV2.1 potassium channel. Electrophysiological studies measuring the impact of the variant on the functional properties of the channel, identified a gain of current, rightward shifts in the steady-state inactivation curve and reduced sensitivity to the blocker, guanxitoxin-1E. Interpretation: The clinical evaluation of this KCNB1 mutation describes a novel variant that is associated with global developmental delays, mild hypotonia and joint laxity, but without seizures. Most of the phenotypic features described are reported for other variants of the KCNB1 gene. However, the absence of earlyonset epileptic disorders is a much less common occurrence. This lack of seizure activity may be because other variants reported have resulted in loss-of-function of the encoded KV2.1 potassium channel, whereas this variant causes a gain-of-function. [ABSTRACT FROM AUTHOR]

Hypospadias is one of the most common congenital malformations, affecting about 4-6 males per 1000 male births, and ranging in severity from a urethral meatus that is slightly off-center to a meatus in the perineal area. Over the past three decades its prevalence may have increased due to changes in reporting of mild cases and/or increased survival of low birth weight infants due to improved neonatal care. However, despite the increasing numbers of males with hypospadias, the overall etiology remains unclear and likely multifactorial in nature. The purpose of this review article is to provide a comprehensive overview of the various factors implicated in hypospadias etiology, including genetic and environmental factors. In addition, we list syndromes in which hypospadias is a relatively common association and delineate the areas that require further investigation in an effort to understand this condition. [ABSTRACT FROM AUTHOR]

Klinefelter syndrome (47,XXY) was initially described in the context of its endocrinologic and physical features; however, subsequent studies have revealed specific impairments in verbal skills and social functioning. Males with sex chromosomal aneuploidies are known to have variability in their developmental profile with the majority presenting with expressive language deficits. As a consequence of language delays, they have an increased likelihood of language-based learning disabilities and social-emotional problems that may persist through adulthood. Studies on males with 47,XXY have revealed unique behavioral and social profiles with possible vulnerability to autistic traits. The prevalence of males with more than one extra sex chromosome (e.g., 48,XXYY and 48,XXXY) and an additional Y (e.g., 47,XYY) is less common, but it is important to understand their social functioning as it provides insight into treatment implications. © 2009 Wiley-Liss, Inc. Dev Disabil Res Rev 2009;15:328–332. [ABSTRACT FROM AUTHOR]

The article offers information about vertex birth molding among newborns. Vertex molding refers to the mechanical changes in fetal head shape, which results from external compression on the cranium and bony adjustments within the cranium. Several factors which influence the individual fetal cranial response include fetal head position and size, gestation age, maternal pelvic shape and dimensions and the quality of uterine contraction. The authors assess that vertex molding sometimes persists beyond the early newborn period, which lead to permanent deformation of head shape. Details about the diagnosis and management of extensive vertex birth molding are presented, as well as seven infants documented with extensive degrees of vertex molding.

Turner syndrome (TS) is among the most common of the sex chromosomal aneuploidies. It results from the absence of one sex chromosome (or part of an X chromosome) in a female, leaving only one X chromosome present in the cell. Primary care physicians should be able to recognize the presenting signs and symptoms of TS, and once the diagnosis is confirmed by a chromosome analysis, they should be able to serve as a valuable source of support for the patient and her family and understand the most current treatments available. [ABSTRACT FROM AUTHOR]

The term Klinefelter syndrome (KS) describes a group of chromosomal disorder in which there is at least one extra X chromosome to a normal male karyotype, 46,XY. XXY aneuploidy is the most common disorder of sex chromosomes in humans, with prevalence of one in 500 males. Other sex chromosomal aneuploidies have also been described, although they are much less frequent, with 48,XXYY and 48,XXXY being present in 1 per 17,000 to 1 per 50,000 male births. The incidence of 49,XXXXY is 1 per 85,000 to 100,000 male births. In addition, 46,XX males also exist and it is caused by translocation of Y material including sex determining region (SRY) to the X chromosome during paternal meiosis. Formal cytogenetic analysis is necessary to make a definite diagnosis, and more obvious differences in physical features tend to be associated with increasing numbers of sex chromosomes. If the diagnosis is not made prenatally, 47,XXY males may present with a variety of subtle clinical signs that are age-related. In infancy, males with 47,XXY may have chromosomal evaluations done for hypospadias, small phallus or cryptorchidism, developmental delay. The school-aged child may present with language delay, learning disabilities, or behavioral problems. The older child or adolescent may be discovered during an endocrine evaluation for delayed or incomplete pubertal development with eunuchoid body habitus, gynecomastia, and small testes. Adults are often evaluated for infertility or breast malignancy. Androgen replacement therapy should begin at puberty, around age 12 years, in increasing dosage sufficient to maintain age appropriate serum concentrations of testosterone, estradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH). The effects on physical and cognitive development increase with the number of extra Xs, and each extra X is associated with an intelligence quotient (IQ) decrease of approximately 15-16 points, with language most affected, particularly expressive language skills. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is the most common inherited cause of mental retardation. Since the initial identification of the responsible gene more than a decade ago, substantial progress has been made in both the clinical aspects of the disorder and its mechanistic basis; hence, it is important for primary care physicians to be familiar with these advances when providing anticipatory guidance. Timely diagnosis allows children to receive early intervention services and families to receive genetic counseling. Here the current state of knowledge is reviewed and a framework is provided for early recognition and diagnosis, along with counseling and treatment implications for the children and family members. [ABSTRACT FROM AUTHOR]

The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1,2). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein. [ABSTRACT FROM AUTHOR]

Recent advances in genetic testing can help to provide a specific diagnosis to children born with syndromes that result in congenital anomalies and developmental delay. One such emerging condition is the 22q13 deletion syndrome. With the introduction of subtelomeric fluorescencein-situ hybridization (FISH) analysis, the 22q13 deletion has become recognized as a relatively widespread and underdiagnosed cause of mental retardation. Primary-care physicians play an important role in the care of children with 22q13 deletion syndrome, from suspecting the diagnosis in a developmentally delayed child through the medical, developmental, and behavioral aspects of their care. Furthermore, they serve as a valuable source of support and advocacy for the family and a resource for other care providers. The remainder of this article addresses the current state of knowledge regarding 22q13 deletion syndrome and offers the primary-care physician a framework in which to provide care and information. [ABSTRACT FROM AUTHOR]

Presents a study which proposed that cerebro-oculo-facio-skeletal syndrome be included within the spectrum of some nucleotide-excision repair disorders. Material and methods; Results; Discussion.

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family (P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients (p = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR (P = 0.113). Comparisons between BRR and a ... [ABSTRACT FROM AUTHOR]

Angelman syndrome (AS) is characterized by mental retardation, absence of speech, seizures and motor dysfunction. AS is caused by maternal deletions for chromosome 15q11-q13, paternal uniparental disomy (UPD), imprinting defects or loss-of-function mutations in the UBE3A locus which encodes E6-AP ubiquitin-protein ligase. The UBE3A gene is imprinted with paternal silencing in human brain and similar silencing of the UBE3a locus in Purkinje cells and hippocampal neurons in the mouse. We have sequenced the major coding exons for UBE3A in 56 index patients with a clinical diagnosis of AS and a normal DNA methylation pattern. The analysis identified disease-causing mutations in 17 of 56 patients (30%) including 13 truncating mutations, two missense mutations, one single amino acid deletion and one stop codon mutation predicting an elongated protein. Mutations were identified in six of eight families (75%) with more than one affected case, and in 11 of 47 isolated cases (23%); no mutation was found in one family with two siblings, one with a typical and one with an atypical phenotype. Mutations were de novo in nine of the 11 isolated cases. An amino acid polymorphism of threonine substituted for alanine at codon 178 was identified, and a 3 bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting with a normal phenotype when a mutation was on the paternal chromosome and an AS phenotype when a mutation was on the maternal chromosome. Laboratory diagnosis and genetic counseling for AS are complex, and mutation analysis is valuable in clinically typical AS patients with a normal methylation analysis. [ABSTRACT FROM AUTHOR]

Focuses on Williams-Beuren syndrome (WBS), an autosomal dominant disorder resulting from a sub-microscopic deletion of contiguous genes on the long arm of chromosome 7. Brief history of the syndrome; Genetics and etiology; Infants with WBS; Other problems associated with the syndrome; Growth; Behavioral characteristics; Natural history and management considerations; Diagnosis.

Focuses on the diagnosis of Chromosome 22q11 deletion syndrome, a human chromosome disorder associated with a wide variety of phenotypic abnormalities. Characteristics; Investigations of specific genes involved in the disorder and their functions; Transmission of the disease; Healthwatch for patients with 22q11 deletion syndrome.

Presents a study on the evaluation and treatment of the deformed ear and malformed auricle. Causative factors; Includes protruding ears and dysplastic auricles; Assessment findings; Surgical and non-surgical treatment.

Abstract. Previous studies of XXY boys suggest that they are at risk for certain communication disorders involving oral and written language. In this study, the language, reading, and spelling skills of a group of 14 XXY boys identified during neonatal cytogenetic screening were compared with those of a group of 15 control children. The two groups were matched for age, grade, race, parity, birth weight, parental age and education, and socioeconomic status. The mean age of the XXY group was 9 years 7 months and that of the control group was 9 years 3 months. The mean academic grade level far both groups was at the transition between third and fourth grade. There was selective reduction in verbal IQ scores for the XXY group and no significant differences apparent between groups for performance IQ scores. The decrease in verbal IQ was associated with a reduced full-scale IQ and also with significant problems in expressive language, auditory processing abilities, and auditory memory. Word-finding difficulties and problems in the production of syntax were major components of the specific expressive language deficit. Except for difficulties in the understanding of Complex sentence structures, the receptive language Skills of XXY boys did not differ significantly from those of the control group. These reductions in speech and language abilities correlated with decreased achievement by the XXY group on a variety of reading and spelling tasks. These results suggest that difficulty learning how to read and spell may be due to a preexistent language disability. Early attention to such expressive language problems may be essential to ameliorate secondary maladaptive behaviors due to chronic language-related learning disabilities. [ABSTRACT FROM AUTHOR]

Abstract. Two groups of 4-year-old children were examined by a dysmorphologist without knowledge of previous examination results or prenatal exposure and categorized as to whether or not they showed fetal alcohol effects. A priori classification of children into the two groups was on the basis of their mothers' self-report of drinking when interviewed during pregnancy. Children born to 108 mothers in a "heavier" drinking group (absolute alcohol concentration is greater than or equal to 30 mL/d [1.0 oz/d]) were compared with a matched group of children born to 97 mothers whose average absolute alcohol concentration was <0.3 mL/d (0.01 oz/d). The percentage of children with fetal alcohol effects in the heavier drinking v the comparison group was 20.4% v 9.3%. When fetal alcohol effects were studied in relation to only the absolute alcohol concentration scores, there was a significantly greater chance of a child being classified as having fetal alcohol effects with increasing levels of alcohol exposure prior to recognition of pregnancy (P = .013). A logistic regression, run on the absolute alcohol concentration scores and other primary exposures, indicated that fetal alcohol effects classification was not significantly related to nicotine, caffeine, or marijuana but was significantly related to absolute alcohol concentration scores even after statistically adjusting for these other exposures (P = .002). Classification of fetal alcohol effects at 4 years of age was compared to a fetal alcohol effects classification obtained at birth by an in dependent dysmorphologist in a sample of 75 subjects examined at both ages, and 80% of the infants classified as having fetal alcohol effects at birth were classified as having fetal alcohol... [ABSTRACT FROM AUTHOR]

Abstract. Most previous cases of unilateral terminal transverse defects of the hand have not been familial. Several previously reported cases of apparent autosomal dominant inheritance of such defects have subsequently been reclassified as type B brachydactyly. We report a pair of adult twin women with unilateral terminal transverse defects affecting the left hand in one woman and the right hand in the other woman. The latter woman has one daughter with a unilateral terminal transverse defect affecting the left hand. The hand anomaly is characterized by absence of the terminal portions of digits 2 to 5 with a mildly hypoplastic thumb (adactylia). Tiny nail remnants are evident on the remaining digital stumps, and no soft tissue syndactyly is apparent. At 2 years of age, the daughter has hypoplastic first, fourth, and fifth metacarpals with no ossification of the second or third metacarpals or any of the phalanges. The affected mother has hypoplastic metacarpals for digits 2 to 4 and a vestigial fifth proximal phalanx on the affected hand, with no other phalanges evident by roentgenogram other than those of the thumb. The mother's twin sister has similar findings, except the ossified phalangeal remnant is on her second and third fingers rather than her fifth finger. Doppler flow arterial patterns appeared normal in each hand of affected family members. The other hand and both feet are clinically and radiologically normal in each case, and the family history is negative for any other individuals with limb anomalies. A review of the literature suggests that this family may very well be unique. Pediatrics 1986;78:103-106; adactylia, hand malformation, genetics, twins, ectrodactyly, terminal transverse limb defect. [ABSTRACT FROM AUTHOR]

Abstract. A patient with 46,XY/69,XXY mixoploidy (a mixture of cell populations whose component cells differ in their chromosome numbers, irrespective of whether these numbers are euploid or aneuploid) who had some clinical manifestations of the Russell-Silver syndrome is reported. Triploidy results in a clinically recognizable lethal syndrome with hydatidiform placental changes, severe intrauterine growth deficiency, dysplastic cranial bones, eye defects, cleft lip and/or palate, malformed ears, micrognathia, syndactyly, genital anomalies and, rarely, spins bifida. Less severe are instances of diploid-triploid mixoploidy and patients are more likely to survive; one of these patients was detected at birth because of asymmetric growth deficiency with syndactyly. Cytogenetic and flow cytometric studies demonstrated absence of triploid cells in peripheral lymphocytes while varying proportions of triploid cells were found in fibroblast cultures derived from each limb. The triploid cell population disappeared with prolonged cell culture. Replication studies with 5-bromodeoxyuridine-DAPI fluorescence revealed two active X chromosomes, and marker chromosomes suggested a paternal origin for the extra haploid set. The following points are emphasized: (1) diploid-triploid mixoploidy can be suspected clinically; (2) the triploid cell population may not be detectable on examination of peripheral blood; (3) the relative degree of asymmetry in the growth deficiency does not appear to relate to the proportion of triploid cells; and (4) both X chromosomes may remain active in the presence of an extra haploid set of chromosomes. Pediatrics 68:23-28, 1981; diploid-triploid mixoploidy, body asymmetry, Russell-Silver syndrome, intrauterine growth retardation, syndactyly. [ABSTRACT FROM AUTHOR]

Abstract. An analysis of 28 dysmorphic offspring with a retrospectively ascertained history of maternal hyperthermia during the first trimester of pregnancy showed a similarity in their pattern of CNS dysfunction and facial dysmorphogenesis. All survivors had mental deficiency and most of them demonstrated altered muscle tone, including hypotonia with increased deep tendon reflexes. Those exposed at four to seven weeks' gestation showed an increased prevalance of facial dysmorphogenesis. The duration of the high fever was usually one or more days, an unusual occurrence during the first trimester of pregnancy. The nature of these defects in relation to the relative timing of hyperthermia exposure is simfiar to that previously noted in animal studies. The morphogenetic implications of these findings are explored and the need for larger, controlled studies is suggested. Pediatrics 67:785-789, 1981; hyperthermia, fever, teratogenesis, malformation, CNS defects, facial defects. [ABSTRACT FROM AUTHOR]

Abstract. A retrospective study of 11 instances of idiopathic coronal craniostenosis in otherwise normal children revealed that early lightening, prolonged moderate to severe pelvic discomfort late in pregnancy, and/ or an abnormal fetal lie were unusual gestational features indicative of intrauterine constraint for eight of these patients. The impression of unusual constraint in utero was further implied by finding associated positional foot deformities in four of these latter eight children. We hypothesize that prolonged constraint of the fetal head may limit anteroposterior growth stretch at the coronal suture and thereby predispose toward early sutural fusion. [ABSTRACT FROM AUTHOR]

C57BL/6J mice, not susceptible to audiogenic seizures (AGS) on the 1st exposure to an acoustic stimulus, were exposed to the acoustic stimulus for 1 mm and then tested at some later date (acoustic priming). They were first exposed at either 8, 16, 19, 22, or 28 days of age, and then tested for AGS 2-16 days after priming. DBA/2J mice, susceptible to AGS on the 1st exposure to intense noise, were exposed to the acoustic stimulus at 26 days of age, and then again 2-14 days later. Data indicate that the incidence of AGS upon the 2nd exposure to the acoustic stimulus is a function of age at priming, the prime-to-test interval in days, and the index of seizures. In the case of DBA mice, later effects are also dependent on the initial level of seizure. [ABSTRACT FROM AUTHOR]

Focuses on the CHARGE association, a pattern of congenital anomalies. Representations of the letters in the acronym; Symptoms and differential diagnosis for CHARGE; Etiology of CHARGE association.

Ren syndrome is a common developmental-neurologic disorder that has been reported almost exclusively in females. Recent work has improved recognition of this condition and helped to clarify the management of this disorder for affected individuals. The primary-care physician can become a major source of support and advocacy for the family of a girl with Rett syndrome. Many other resources are available to the primary care giver and the families of children with Rett syndrome; these may help to provide early diagnosis, psychological support, and preventive medical care for these individuals. The current state of knowledge regarding Rett syndrome is reviewed and a framework is provided for medical and developmental interventions. [ABSTRACT FROM AUTHOR]

Attempts to study the genetics of human thumb polydactyly have been hampered by Lack of awareness of the extremely varied expression of upper Limb preaxial anomalies. It has been appreciated that thumb polydactyly could range from a broadened distal phalanx to complete duplication of the entire thumb. Most cases are sporadic and unilateral, but rare familial cases with wide variability and occasional nonpenetrance have been described. Four unrelated families are described who have thumb polydactyly as part of the range of expression for a dominant gene that is frequently associated with absence of thenar intrinsic muscles and flexor pollicis longus with inability to flex the thumb across the palm (the Fromont anomaly). These families and previous literature reports suggest that expression of the gene can range from thumb hypoplasia (most commonly the Fromont anomaly) to triphalangeal thumb or thumb polydactyly. As a consequence of this experience, we urge that parents, siblings, and other close relatives of patients born with thumb polydactyly be carefully examined for mild degrees of thumb hypoplasia or any other thumb anomaly, and that these findings be considered when providing recurrence risk counseling. [ABSTRACT FROM AUTHOR]

The linear growth data of 48 XY individuals, presumed to be androgen-insensitive as a consequence of the testicular feminization syndrome were found to be similar to normal male standards and tall for normal female standards. These data are interpreted as evidence for one or more Y-linked gene function(s) which augment stature independently of testosterone effects. [ABSTRACT FROM AUTHOR]