Joy Samanich

Osteopathia striata congenita with cranial sclerosis and intellectual disability due to contiguous gene deletions involving the WTX locus

Osteopathia striata congenita with cranial sclerosis (OSCS) is a skeletal dysplasia caused by germline deletions of or truncating point mutations in the X‐linked gene WTX (FAM123B, AMER1). Females present with longitudinal striations of sclerotic bone along the long axis of long bones and cranial sclerosis, with a high prevalence of cleft palate and hearing loss. Intellectual disability or neurodevelopmental delay is not observed in females with point mutations in WTX leading to OSCS. One female has been described with a deletion spanning multiple neighbouring genes suggesting that deletion of some neighbouring loci may result in abnormal neurodevelopment. In this cohort of 13 females with OSCS resulting from deletions of WTX, a relationship is observed where deletion of ARHGEF9 and/or MTMR8 in conjunction with WTX results in an additional neurodevelopmental phenotype whereas deletion of ASB12 along with WTX is associated with a good neurodevelopmental prognosis.

Spectrum of elastin sequence variants and cardiovascular phenotypes in 49 patients with Williams–Beuren syndrome†

Haploinsufficiency of the elastin gene (ELN) on 7q11.23 is responsible for supravalvular aortic stenosis (SVAS) and other arteriopathies in patients with Williams–Beuren syndrome (WBS). These defects occur with variable penetrance and expressivity, but the basis of this is unknown. To determine whether DNA variations in ELN could serve as genetic modifiers, we sequenced the 33 exons and immediately surrounding sequence of the ELN gene (9,455 bp of sequence) in 49 DNAs from patients with WBS and compared cardiovascular phenotypes. Four missense, and four novel intronic variants were identified from a total of 24 mostly intronic single nucleotide variations and one indel. Two missense changes were present in one patient each, one published, p.Gly610Ser in exon 27 (MAF, 0.003) and one novel, p.Cys714Tyr, in exon 33 (MAF, 0.001), were rare in the general population. To identify a statistical association between the variants identified here and cardiovascular phenotypes a larger cohort would be needed.

Agnathia–otocephaly complex: A case report and examination of the OTX2 and PRRX1 genes

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.

Molecular characterization of an interstitial deletion of 1p31.3 in a patient with obesity and psychiatric illness and a review of the literature

We report on the clinical and array‐based characterization of an interstitial 1p31.3 deletion in a 15‐year‐old male patient with obesity, behavioral problems including multiple psychiatric diagnoses, mild intellectual impairment, facial dysmorphism, and a strong family history of psychiatric illness. The deletion breakpoints were determined by molecular karyotyping, revealing a 3.2 Mb excision. Patients previously reported with hemizygous deletions including this cytogenetic band had intellectual impairment and some facial features that overlap with our patients phenotype. However, their deletions were larger, encompassing several cytogenetic bands, making this case the smallest deletion to date that we are aware of sharing these phenotypic characteristics. There are 17 genes that map to the interval. Two genes within the interval, LEPR and PDE4B, are interesting candidates for these phenotypes because of their potential role in obesity and psychiatric illness, respectively. Identification of the smaller deletion underscores the importance of combining clinical investigation and array comparative genomic hybridization analysis for appropriate diagnosis, genetic counseling and potentially for prenatal diagnosis.

Severe osteopathia striata with cranial sclerosis in a female case with whole WTX gene deletion

Osteopathia striata with cranial sclerosis (OSCS) is caused by truncating mutations or deletions in the X linked gene, WTX, and is characterized by sclerotic striations of the metaphyses and diaphyses of long bones, pelvis, and scapula, along with craniofacial hyperostosis. Females typically manifest with craniofacial dysmorphisms including macrocephaly, hypertelorism, depressed nasal bridge, and hypoplastic maxilla, often have cleft palate, and less often extra skeletal anomalies. Here we report on a sporadic female patient with OSCS born at 33 weeks, with coarse facies, an abnormal head shape, cleft palate, pyloric stenosis, a small VSD, and laryngotracheomalacia sufficiently severe to require tracheostomy placement. Characteristic radiologic findings were apparent on skeletal survey and cranial CT. At age 5, she showed mild delays in neurodevelopmental milestones. A deletion of WTX and the adjacent gene ASB12 was detected via MLPA and there was no skewing of the X‐chromosome inactivation pattern (58:42). Neurodevelopmental delays can manifest in females with OSCS and deletions at the WTX locus, but deletion of the ASB12 gene in this case suggests it is unlikely to contribute to the pathogenesis of this complication. Implication of ASB12 in the patients other unique features such as laryngotracheomalacia and pyloric stenosis is also unlikely. This case illustrates an early presentation of severe OSCS in a female without skewing of the X‐chromosome inactivation pattern, emphasizing the variable expressivity of this disorder.

Dextrocardia, atrial septal defect, severe developmental delay, facial anomalies, and supernumerary ribs in a child with a complex unbalanced 8;22 translocation including partial 8p duplication.

We report on a child with dextrocardia, atrial septal defect (ASD), severe developmental delay, hypotonia, 13 pairs of ribs, left preauricular choristoma, hirsutism, and craniofacial abnormalities. Prenatal cytogenetic evaluation showed karyotype 46,XY,?dup(8p)ish del(8)pter. Postnatal array CGH demonstrated a 6.8 Mb terminal deletion at 8p23.3–p23, an interstitial 31.1 Mb duplication within 8p23.1–p11, and a terminal duplication of 0.24 Mb at 22q13.33, refining the karyotype to 46,XY,der(8)dup(8)(p23.1p11.1)t(8;22)(p23.1;q13.1).ish der(8)dup(8)(p23.1p11.1)t(8;22)(p23.1;q13.1) (D8S504‐,MS607 + ,ARSA + ,D8Z1 + , RP115713 + +). Previous reports of distal 8p deletion, 8p duplication, and distal 22q duplication have shown similar manifestations, including congenital heart disease, intellectual impairment, and multiple minor anomalies. We correlate the patients clinical findings with these particular areas of copy number. This case study supports the use of aCGH to identify subtle chromosomal rearrangement in infants with cardiac malformation as their most significant or only apparent birth defect. Additionally, it illustrates why aCGH is essential in the description of chromosome rearrangements, even those seemingly visible via routine karyotype. This method shows that there is often greater complexity submicroscopically, essential to an adequate understanding of a patients genotype and phenotype.

Erratum: A novel C-terminal CIB2 (Calcium and Integrin Binding Protein 2) mutation associated with non-syndromic hearing loss in a hispanic family (PLoS ONE (2015) 10:10 (e0133082) DOI: 10.1371/journal.pone.0133082)

Hearing loss is a complex disorder caused by both genetic and environmental factors. Previously, mutations inCIB2 have been identified as a common cause of genetic hearing loss in Pakistani and Turkish populations. Here we report a novel (c.556C>T; p.(Arg186Trp)) transition mutation in theCIB2 gene identified through whole exome sequencing (WES) in a Caribbean Hispanic family with non-syndromic hearing loss. CIB2 belongs to the family of calciumand integrin-binding (CIB) proteins. The carboxy-termini of CIB proteins are associated with calcium binding and intracellular signaling. The p.(Arg186Trp) mutation is localized within predicted type II PDZ binding ligand at the carboxy terminus. Our ex vivo studies revealed that the mutation did not alter the interactions of CIB2 with Whirlin, nor its targeting to the tips of hair cell stereocilia. However, we found that themutation disrupts inhibition of ATP-induced Ca responses by CIB2 in a heterologous expression system. Our findings support p. (Arg186Trp) mutation as a cause for hearing loss in this Hispanic family. In addition, it further highlights the necessity of the calcium binding property of CIB2 for normal hearing.

Interstitial duplication of 22q13.2 in a girl with short stature, impaired speech and language, and dysmorphism

The 22q13.3 deletion syndrome has been widely reported, with a known phenotype including global developmental delay, normal to accelerated growth and a characteristic facial appearance. A duplication syndrome involving this region has also been reported, with a somewhat more variable phenotype including psychomotor retardation, growth restriction, characteristic facial appearance differing from that seen in the deletion syndrome, and multiple malformations. The majority of reported patients have terminal duplications, with only three previous reports of interstitial duplication of the region. Herein we report a young woman with a de novo 569 kb interstitial duplication of 22q13.2 and short stature, speech and language impairment, refractive amblyopia, menorrhagia and facial dysmorphism. Comparison of her phenotype to previously reported patients with interstitial duplications reveals common traits including growth restriction, craniofacial anomalies and developmental delays. Included in the duplicated region is the gene EP300, mutations and deletions of which are implicated in Rubinstein-Taybi syndrome and thyrotroph embryonic factor, which has been proposed to be related to the pituitary hypoplasia seen in one patient with a large duplication, and several other genes without clear relation to disease.

The clinical and genetic distinction between familial supravalvular aortic stenosis (Eisenberg syndrome) and Williams-Beuren syndrome

Sir, Recently, an article about Williams-Beuren syndrome [1] appeared in Pediatric Radiology. Characteristic facies, intellectual disability, as well as supravalvular aortic stenosis (SVAS) are typical of Williams syndrome (WS) (OMIM #194050). Familial aortic stenosis, or Eisenberg syndrome [2] (OMIM#185500), represents a separate group of patients with autosomal-dominant SVAS in which affected members have normal facies and average intelligence. The history of Eisenberg-type familial SVAS and WS, once considered part of a single condition, is an interesting one. Because of the commonality of the cardiac lesion in these two groups, advances in the genetic basis of Eisenbergtype familial SVAS led to the discovery that both WS and familial SVAS result from an abnormality in the elastin gene (ELN). In 1993 Keating [3], a molecular geneticist, used linkage analysis to suggest that ELN, located at 7q11.23, was the candidate gene for SVAS. Later publications identified several families with familial SVAS in whom the ELN gene was disrupted by either a small deletion or translocation. Based on the identification of the genetic abnormality present in familial SVAS, fluorescent in situ hybridization (FISH) analysis of patients with the WS phenotype was performed, and complete deletion of the ELN genewas identified. Haploinsufficiency of additional genes has been implicated in the other abnormalities characteristic of WS. The history of familial SVAS and its relationship toWS has been largely forgotten. Recent interest in the genetic cause of WS is directly related to the genetic breakthroughs in patients with isolated familial SVAS. Because of the commonality of the cardiac lesion in these two groups, advances in one disease led to discoveries in the second.

Health care supervision for twin pairs

Twins are at increased risk for congenital anomalies and have particular health care needs, but twin management guidelines do not exist. This review attempts to integrate the latest research findings and evidence‐based medicine on twins into basic clinical recommendations for general pediatricians.