Carol E. Anderson

Characterisation of deletions of the ZFHX1B region and genotype-phenotype analysis in Mowat-Wilson syndrome

In 1998, Mowat et al 1 delineated a syndrome with Hirschsprung disease (HSCR) or severe constipation, microcephaly, mental retardation, and a distinctive facial appearance.1 Because two of the patients had a cytogenetically visible deletion of 2q22-q23,1,2 and all patients were sporadic cases, a contiguous gene syndrome or a dominant single gene disorder involving this locus were suggested.1 Two similar patients with cytogenetically balanced translocation t(2;13)(q22;q22) and t(2;11)(q22.2;q21), respectively, allowed Wakamatsu et al 3 and Cacheux et al 4 to narrow down the critical interval to 5 Mb and to one single gene respectively, which led both groups independently to the detection of intragenic mutations in the gene coding for Smad interacting protein-1 (formerly SIP1 , now called zinc finger homeobox 1B ( ZFHX1B )) in patients with so called “syndromic HSCR”. However, because HSCR is not an obligatory symptom and patients with and without HSCR can be recognised by other features, especially their distinct facial gestalt,5,6 we suggested that “Mowat-Wilson syndrome” (MWS) is a more appropriate name.6 Although the developmental ZFHX1B expression pattern fully explains the clinical spectrum observed in patients with Mowat-Wilson syndrome by haploinsufficiency of this gene alone,5,7 Wakamatsu et al 3 initially stated that their deletion patient would have a more severe phenotype and therefore would have a contiguous gene syndrome. Amiel et al 8 reported that the phenotype was similar in patients with “syndromic HSCR” caused by mutations and cytogenetically non-visible large scale deletions of the ZFHX1B locus, respectively, but the deletion sizes were not delineated. We therefore analysed deletion size and genotype-phenotype correlation in four new patients with cryptic deletions of the ZFHX1B locus. ### Key points

5q14.3 Deletion Manifesting as Mitochondrial Disease and Autism: Case Report

Mitochondrial disorders are usually associated with defects of 1 or more of the 5 complexes (I to V) of the electron transport chain, or respiratory chain. Complex I and IV are the 2 most frequent abnormalities of the electron transport chain in humans. The authors report the case of a 12-year-old boy with dysmorphic facies, mental retardation, autism, epilepsy, and leg weakness. Buccal swab electron transport chain analysis revealed severe decrease in complex IV and mild reduction in complex I activity levels. Chromosomal microarray studies, using array-based comparative genomic hybridization, revealed a 1-Mb deletion in the 5q14.3 region. This case illustrates that this deletion can be associated with complex I and IV deficits, hence manifesting as a mitochondrial disease. It could be hypothesized that genes that either encode or regulate the expression and/or assembly of complex IV or I subunits are located within the deleted region of 5q14.3.

Prenatal zidovudine use and congenital anomalies in a Medicaid population

Objectives: To examine the association of prescribed zidovudine (ZDV) during pregnancy with congenital anomalies in a population‐based cohort. Methods: Medicaid claims were used to assess prescribed ZDV and children’s major congenital anomalies in 1932 liveborn deliveries from 1993 to 1996 to HIV‐infected women in the state of New York (NYS), U.S.A.. Prevalence of anomalies in the cohort was compared with that of a general NYS population. Within the cohort, adjusted odds of any anomaly were compared by receipt of ZDV and by trimester of first prescription. Results: The adjusted prevalence of any anomaly in the study cohort was 2.76 times greater than in the general population (95% confidence interval [CI], 2.36‐3.17). Children of study women who were prescribed ZDV had increased adjusted odds of any anomaly (adjusted odds ratio [OR], 1.55; 95% CI, 1.01‐2.29). Adjusted ORs (with CIs) by trimester of first prescription were 1.20 (0.58‐2.51), 1.47 (0.85‐2.55), and 1.84 (1.04‐3.25) for the first, second, and third trimesters, respectively. Conclusion: Children of HIV‐infected women in this cohort had a greater prevalence of major anomalies than did the general NYS population. An increased risk of major anomalies was not evident for first trimester exposure when the association would have been most biologically plausible.

A report of three patients with an interstitial deletion of chromosome 15q24

Partial monosomy of the q2 region of chromosome 15 has been infrequently reported. Moreover, interstitial deletions involving 15q22‐q24 have been described in only nine patients to date. The phenotype of these reported individuals is subject to the extent of the deletion but typically includes altered muscle tone and significant developmental delays. In addition, eye abnormalities, such as strabismus, microphthalmia, or colobomas, ear abnormalities including cleft earlobe and preauricular tags, and urogenital defects are common features. Congenital heart defects, diaphragmatic hernia, abnormalities of the central nervous system, and skeletal anomalies have been reported but appear to be less frequent clinical manifestations. In this report, we describe three new patients with interstitial deletions involving 15q24, two with cryptic deletions identified by fluorescence in situ hybridization (FISH) with a probe for the PML gene and one with a cytogenetically visible deletion of 15q22.3‐q24. The clinical presentation of these individuals is similar to those previously described and includes global developmental delays, hypotonia, and genital abnormalities in the males. The identification of these three cases demonstrates that the above clinical features are associated with a new cytogenetic deletion syndrome. Furthermore, we suggest that FISH analysis with a probe for the PML gene be performed in patients with these physical findings.

Expanding the SHOC2 Mutation Associated Phenotype of Noonan Syndrome with Loose Anagen Hair: Structural Brain Anomalies and Myelofibrosis

Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2‐year‐old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis.

Characterization of a Wilms tumor in a 9-year-old girl with trisomy 18

This is a report of a trisomy 18 patient who developed Wilms tumor in conjunction with perilobar nephroblastomatosis (NB) at 9 years and 5 months of age. Review of the literature revealed that most patients with trisomy 18 who develop Wilms tumor, do so at a later than expected age for a tumor related to NB, and are females. In this case, no chromosome 11 WT1 mutation was detected by PCR/SSCP analysis, but the tumor had in addition to the trisomy, an isochromosome 7q and loss of heterozygosity at 16q, two mutations that have been linked independently to Wilms tumorigenesis.

Microarray analysis in children with developmental disorder or epilepsy.

The technique of chromosomal microarray analysis identifies genetic imbalance. Evaluation of its diagnostic role in pediatrics is still underway. We describe our experience with chromosomal microarrays. We retrospectively reviewed the charts of children in the Sections of Neurology and Clinical Genetics at St. Christophers Hospital for Children who had undergone microarray analysis between 2006 and 2009. Collected data included age, sex, and the presence of mental retardation, developmental delay, autism, learning disability, hypotonia, dysmorphic features, and epilepsy, and the use of microarray technique. Statistical analysis was performed using SPSS. There were 82 children (mean age ± S.D., 5.7 ± 5 years), including 45 (55%) boys and 37 (45%) girls. All patients exhibited a normal karyotype. Microarray analysis produced abnormal results in 20 (23.5%). Deletions comprised 74% of all abnormalities. Patients with ≥ 4 clinical variables demonstrated a 30.5% incidence of abnormal chromosomal microarray findings, compared with 8.7% of patients with ≤ 3 clinical variables (P = 0.039, χ(2) test). Logistic regression indicated that motor impairment (P = 0.039) and presence of epilepsy (P = 0.024) independently contributed to the model. The likelihood of an abnormal microarray result increased with the number of clinical abnormalities. Microarray analysis will likely become the diagnostic genetic test of choice in children with neurodevelopmental disorders or epilepsy.

Fraternal Twins With Autism, Severe Cognitive Deficit, and Epilepsy: Diagnostic Role of Chromosomal Microarray Analysis

A 7-year-old child presented with atypical absence epilepsy. He also had autism and severe cognitive deficit. As part of his diagnostic workup, a chromosomal microarray analysis was performed, which showed novel biallelic deletions in the neurexin 1 gene (NRXN1). His fraternal twin sister, who also had autism and cognitive impairment, was subsequently found to have the same biallelic deletions. Deletions included a 272-282kb loss at band 2p16.3 in one allele and a smaller 135-174-kb loss on the second allele. Neurexin 1 (NRXN1) is a cell adhesion protein, forming a synaptic complex with neuroligin. This signals a pathway that is critical for activity-dependent synaptic transmission. Mutations in this gene have been associated with autism and neurodevelopmental delay. Although there are many reports of heterozygous mutations with variable expressivity, only 3 cases with biallelic NRXN1 mutations have been previously reported, all of which have a more severe phenotype. We report 2 siblings with biallelic deletions, both of which affect the promoter region and exons 1-5 in the α-NRXN1 isoform, which has a role in the Ca(2+)-dependent release of neurotransmitters in the central nervous system. Our cases expand the phenotype of biallelic α NRXN 1 mutations and emphasize the important role of NRXN1 in autism and intellectual disability. Chromosomal microarray analysis should be the clinical standard in all specialties for first-tier genetic testing in autistic spectrum disorders.

Co‐occurrence of non‐mosaic trisomy 22 and inherited balanced t(4;6)(q33;q23.3) in a liveborn female: Case report and review of the literature

Trisomy 22 is the third most common autosomal trisomy occurring in about 0.4% of all clinically recognized pregnancies. Complete non‐mosaic trisomy 22 is extremely rare in live births. Most affected children die before one year of age. To date, only 29 liveborn cases have been reported and none has carried an additional genetic lesion. In this report, we describe the clinical presentation, cytogenetic, and cytogenomic findings in a liveborn female with complete non‐mosaic trisomy 22 as well as a paternally inherited, balanced reciprocal chromosomal rearrangement t(4;6)(q33;q23.3). The proband manifested features commonly seen in individuals with non‐mosaic trisomy 22 such as intrauterine growth retardation (IUGR), single umbilical artery, cranial abnormalities, short neck, cleft lip and palate, dysmorphic ears, hypoplastic nipples, digital malformation, congenital heart defects, dysplastic kidneys, and genital anomalies. In addition, she had lobar holoprosencephaly, aqueductal stenosis, and limb and eye problems that have not been associated with complete trisomy 22 in previous reports. She died at 35 days of age of complex heart disease and renal failure. We are hereby expanding the cytogenetic and clinical spectrum of this rare chromosome disorder. Clinical features of liveborn children with non‐mosaic trisomy 22 are reviewed and compared to those in our proband. The impact of genomic content in relation to the survival of trisomies in humans is also discussed.

Improvement of pancytopenia and thrombocytopenia with decreasing mosaicism for isochromosome Xp

We report the unique association of variable constitutional mosaicism 46,X, i(X)(p10)/46,XX with recurrent thrombocytopenia in a child with failure to thrive and apnea in infancy. Her bone marrow had equal distribution of the normal and abnormal cell lines at diagnosis, at nearly 6 years of age. Improvement of her pancytopenia and thrombocytopenia was concurrent with a decreasing level of mosaicism observed in multiple studies over the next 3 years. This suggests that extra copies of genes on the p‐arm are inhibitory to blood cell maturation, with long‐term selection against the i(Xp)‐containing cells. Pediatr Blood Cancer 2009;52:650–652.