Maureen Holvoet

Cri du chat syndrome: Changing phenotype in older patients

The cri du chat syndrome or 5p deletion syndrome is a well-delineated clinical entity and has an incidence of 1/50,000 in newborn infants. A de novo deletion is present in 85% of the patients. Ten to 15% are familial cases with more than 90% due to a parental translocation and 5% due to an inversion of chromosome 5. Although the size of the deleted segment varies, the critical segment that is deleted in all patients appears to be 5p15.2. The clinical picture is well known in younger patients and includes the typical high-pitched cry, psychomotor retardation, microcephaly, growth rate failure, and craniofacial abnormalities including round face, hypertelorism, broad nasal bridge, downward slanting palpebral fissures, and micrognathia. With advancing age, the clinical picture becomes less striking. We present seven patients with 5p deletion syndrome, who were between age 16 and 47 years. Comparing their phenotype at several ages, a change of their phenotype was noted. Some of the clinical characteristics became more evident such as long face, macrostomia, and scoliosis. All patients were severely or profoundly mentally retarded except one patient who was mildly mentally retarded. The diagnosis was difficult to make in some of the patients who were first seen at an older age. In some of them, the craniofacial appearance resembled that seen in Angelman syndrome. Most patients had periods of destructive behavior, self mutilation, and aggression. The clinical diagnosis should be confirmed as soon as possible with cytogenetic investigation to provide specific support, prevention, and treatment of complications. Therefore, it is important to perform follow-up studies in young children to determine their outcome after infant-stimulation programs.

Recurrent De Novo Mutations in PACS1 Cause Defective Cranial-Neural-Crest Migration and Define a Recognizable Intellectual-Disability Syndrome

We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.

A recognisable behavioural phenotype associated with terminal deletions of the short arm of chromosome 8

We report the clinical findings in 5 patients with a terminal deletion of the short arm of chromosome 8. Mild developmental delay was constantly present, in association with microcephaly in 4 of 5 patients. Facial anomalies were mild or absent. A congenital heart defect was present in 3 patients: an atrioventricular septal defect (AVSD) in 2 and an atrial septal defect type II (ASDII) with pulmonary stenosis in one. A highly similar pattern of behavioural difficulties was present in the 3 older children (8-11 years), with outbursts of aggressiveness and destructive behaviour. Follow-up in one patient showed that at the age of 16 years, these behavioural problems had largely disappeared. This observation suggests that in addition to mental retardation, microcephaly, congenital heart defect (typically AVSD), a terminal deletion of chromosome 8p may be associated with a characteristic behavioural phenotype during childhood.

Partial DiGeorge syndrome in two patients with a 10p rearrangement

We describe 2 patients with a partial DiGeorge syndrome (facial dysmorphism, hypoparathyroidism, renal agenesis, mental retardation) and a rearrangement of chromosome 10p. The first patient carries a complex chromosomal rearrangement, with a reciprocal insertional translocation between the short arm of chromosome 10 and the long arm of chromosome 8, with karyotype 46, XY ins(8;10) (8pter→8q13::10p15→10p14::8q24.1→8qter) ins(10;8) (10pter→10p15::8q24.1→8q13::10p14→10qter). The karyotype of the second patient shows a terminal deletion of the short arm of chromosome 10. In both patients, the breakpoints on chromosome 10p reside outside the previously determined DiGeorge critical region II (DGCRII). This is in agreement with previous reports of patients with a terminal deletion of 10p with breakpoints distal to the DGCRII and renal malformations/hypoparathyroidism, and thus adds to evidence that these features may be caused by haploinsufficiency of one or more genes distal to the DGCRII.

Trisomy 15 rescue with jumping translocation of distal 15q in Prader-Willi syndrome.

We report a patient with Prader-Willi syndrome (PWS) and mosaicism for a de novo jumping translocation of distal chromosome 15q, resulting in partial trisomy for 15q24-qter. A maternal uniparental heterodisomy for chromosome 15 was present in all cells, defining the molecular basis for the PWS in this patient. The translocated distal 15q fragment was of paternal origin and was present as a jumping translocation, involving three different translocation partners, chromosomes 14q, 4q, and 16p. The recipient chromosomes appeared cytogenetically intact and interstitial telomere DNA sequences were present at the breakpoint junctions. This strongly suggests that the initial event leading to the translocation of distal 15q was a non-reciprocal translocation, with fusion between the 15q24 break-point and the telomeres of the recipient chromosomes. These observations are best explained by a partial zygotic trisomy rescue and comprise a previously undescribed mechanism leading to partial trisomy.

ARX mutation in a boy with transsphenoidal encephalocele and hypopituitarism

To the Editor: The Aristaless-related homeobox gene, ARX, has been implicated in X-linked mental retardation (MR) associated with a wide range of neurological manifestations, including Partington syndrome (MIM 309510) (1), myoclonic epilepsy, X-linked West syndrome (MIM308350), andX-linked lissencephaly with abnormal genitalia (MIM 300215) (2–4). The observed phenotypes correlate closely to the type and localization of the mutations found. Polyalanine expansions in one of the two polyalanine tracts in exon 2, and non-conservative missense mutations were identified in the milder dystonia and epilepsy phenotypes. In contrast, null mutations and conservative missense mutations result in severe brain malformation in humans and mice (4). Thus far, the polyalanine tract expansion is the most frequently occurring mutation, and interfamilial as well as intrafamilial variability are observed (5, 6). Here, we present a boy with an ARX polyalanine expansion, MR, transsphenoidal encephalocele, agenesis of the corpus callosum (ACC) and a hypothalamic variant of partial anterior hypopituitarism, adding a new phenotype to the list of clinical presentations associated with mutations in the ARX gene. He belongs to a family with four males with variable MR that was ascertained by systematic follow-up of patients with MR and congenital anomalies. The index patient is currently in adolescence and was initially reported at the age of 6 months by Grubben et al. (7). In summary, he was born after an uneventful pregnancy, with a median cleft lip and palate and a transsphenoidal encephalocele (Fig. 1). Partial anterior hypopituitarism was documented in early infancy consisting of hypothyroidism and growth hormone (GH) deficiency. The hypothalamic origin of this partial variant of anterior hypopituitarism was corroborated by documenting normal pituitary responses to GH-releasing hormone and thyrotropin-releasing hormone, respectively. Early virilization (Tanner: G2) and testicular enlargement were observed at the age of 13 years, indicating that the gonadotropic axis is at least partially functional. Magnetic resonance imaging scan showeda frontobasal transsphenoidal encephalocele extending into the epipharynx, together with ACC and dilated occipital horns (Fig. 1). The palate was surgically closed at the age of 5 years, and throughout childhood, a global psychomotor delay was noted (TIQ of 56). His facial characteristics are shown in Fig. 1. His elder brother is currently aged 20 and is moderately mentally retarded. Besides a macrocephaly, no other abnormalities are present. Two brothers of the mother also present with moderateMR. One of them also features dysarthria and dystonic movements of the hands, known as Partington syndrome (Fig. 1). There is no history of epilepsy in the four affected men. Mutation analysis of ARX showed the presence of the 24-basepair duplication in all four males and the normal carrier female. Congenital basal encephaloceles are very rare anomalies (one in 35,000 live births) and are classified in four types of which the transsphenoidal type is the least frequent (8, 9). They arise before the 10th week of gestation, and different theories on the pathogenesis have been proposed, including failure of fusion of ossification centres, failure of separation of neuro-ectodermal elements from the neural crest, and persistence of the craniopharyngeal canal (10, 11). Interestingly, expression of ARX is noted in the developing maxilla in mouse (K. Poirier, personal communication), and protein dysfunction could interfere with normal fusion of ossification centres. The most frequently associated clinical features are hypothalamic-pituitary dysfunction, midfacial anomaly, ACC, and optic nerve anomaly (11–14). The reported endocrine defects associated with basal encephalocele are variable and involve mostly the anterior pituitary hormones (15). In this case, neuroendocrine testing disclosed an hypopituitarism of hypothalamic origin. This variant is compared to the hypopituitarism observed in HESX-1 mutants, rather than to the primarily pituitary forms observed in Pit-1, Clin Genet 2004: 65: 503–505 Copyright # Blackwell Munksgaard 2004 Printed inDenmark. All rights reserved CLINICALGENETICS doi: 10.1111/j.1399-0004.2004.00256.x

Triplication of distal chromosome 10q.

We describe a patient with a de novo chromosomal aberration with karyotype 46,XY,10q+, presenting clinical features of partial duplication of distal chromosome 10q. Further studies using microsatellites and FISH showed a triplication of distal chromosome 10q. The rearrangement involved both maternal homologues and the middle chromosomal 10q fragment of the triplication was inverted, similar to previously reported chromosomal triplications. Chromosomal triplications may be more frequent than assumed and may share a common molecular mechanism.

A microduplication of CBP in a patient with mental retardation and a congenital heart defect

Rubinstein–Taybi syndrome is a well‐characterized genetic syndrome caused by haploinsufficiency of CBP in a majority of individuals. In 10% of cases a microdeletion in 16p13.3 affecting CBP is detected. We report on a patient with a de novo 345–480 kb micro‐duplication the region, encompassing only CBP and TRAP1. This boy presented with various minor physical anomalies, moderate mental retardation, and an atrial septal defect, but none of the other typical characteristics of the Rubinstein–Taybi syndrome, such as the broad thumbs and first toes or facial characteristics. This finding implicates CBP as one of the causative genes for the trisomy 16p13 syndrome, and indicates this is a contiguous gene syndrome.

Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern.

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X‐linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X‐inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X‐inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole‐exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X‐inactivation presumably cause both XLID and skewing of X‐inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X‐linked variants in female patients.

Regional localization of two genes for nonspecific X-linked mental retardation to Xp22.3-p22.2 (MRX49) and Xp11.3-p11.21 (MRX50).

Two families with nonspecific X-linked mental retardation (XLMR) are presented. In the first family, MRX49, 5 male patients in 2 generations showed mild to moderate mental retardation. Two-point linkage analysis with 28 polymorphic markers, dispersed over the X-chromosome, yielded a maximal LOD score of 2.107 with markers DXS7107 and DXS8051 at theta = 0.0, localizing the MRX49 gene at Xp22.3-p22.2, between Xpter and marker DXS8022. Multipoint linkage analysis showed negative LOD values over all other regions of the chromosome. In the second family, MRX50, 4 males in 2 generations showed moderate mental retardation. Pairwise linkage analysis with 28 polymorphic markers yielded a LOD score of 2.056 with markers DXS8054, DXS1055, and DXS1204, all at theta = 0.0. Flanking markers were DXS8012 and DXS991, situating the MRX50 gene at Xp11.3-Xp11.21, in the pericentromeric part of the short arm of the X chromosome.