Carol L. Clericuzio

Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants

BACKGROUND Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02). CONCLUSIONS Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).

A new form of long QT syndrome associated with syndactyly

OBJECTIVES The purpose of this study was to characterize a possible association between long QT syndrome and syndactyly. BACKGROUND Long QT syndrome causes syncope and sudden death from ventricular arrhythmias. Syndactyly is a developmental disorder that causes webbing of the hands and feet. Both disorders can be inherited as isolated, autosomal dominant traits, but an association between them has not been established. METHODS We identified three children with long QT syndrome, atrioventricular (AV) block and simple syndactyly. Phenotypic and laboratory data were obtained from families, attending physicians and medical records. RESULTS All patients had bilateral cutaneous syndactyly and were diagnosed with long QT syndrome within the 1st 2 years of life. Structural heart disease, particularly a patent ductus arteriosus, was present in all three patients. Analysis of electrocardiograms showed marked prolongation of the QT intervals with rate-corrected QT intervals of 633, 628 and 680 ms, respectively. Transient AV block was also noted. Two of the three children died suddenly despite treatment with beta-adrenergic blocking agents and permanent pacing. CONCLUSIONS We postulate that these children have a new form of long QT syndrome associated with syndactyly and a high risk of sudden death. The association of syndactyly with long QT syndrome may provide insight into the mechanisms underlying both disorders. Patients with syndactyly should be evaluated for the presence of long QT syndrome, and if it is found, aggressive treatment may be warranted.

Unexpected death and critical illness in Prader-Willi syndrome: report of ten individuals.

Individuals with Prader–Willi syndrome (PWS) generally survive into adulthood. Common causes of death are obesity related cor pulmonale and respiratory failure. We report on a case series of eight children and two adults with unexpected death or critical illness. Our data show age‐specific characteristics of PWS patients with fatal or life‐threatening illnesses. Under the age of 2 years, childhood illnesses in general were associated with high fever and rapid demise or near‐demise. Hypothalamic dysfunction likely plays a role in exaggerated fever response, but also perhaps in central regulation of adrenal function. Below average sized adrenal glands were found in three children, which raises the possibility of unrecognized adrenal insufficiency in a subset of individuals with PWS and emphasizes the vital role of autopsy. The tub drowning death of an adult patient could be related to central hypersomnia, which has been reported in PWS. We suggest that increased risk for critical illness be considered in the discussion of anticipatory guidance for the care of infants with PWS. Since a number of children died while hospitalized, particularly close observation of PWS children who are ill enough to warrant hospital admission is recommended.

Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)

Objective To identify genetic causes of COACH syndrome Background COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). Methods In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. Results 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). Conclusions Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.

Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP–HHT syndrome†

Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP–HHT was described that is also caused by mutations in SMAD4. Although both JP and JP–HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP–HHT patients were clustered in the COOH‐terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre‐symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP–HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP–HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP–HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP–HHT and monitored accordingly.

Emotion-related learning in individuals prenatally exposed to alcohol: an investigation of the relation between set shifting, extinction of responses, and behavior

The association between deficits in emotion-related learning, conceptual set shifting, and behavioral problems was investigated in individuals with substantial prenatal alcohol exposure. Twenty subjects with confirmed prenatal alcohol exposure (10 of whom were diagnosed as having Fetal Alcohol Syndrome) and 20 normal controls matched for age, gender, and ethnic background participated. The two groups were administered a battery of tests including two tests of emotion-related learning (visual discrimination reversal and extinction of reward-response associations), tests of conceptual set shifting and intellectual ability, and behavioral measures. The alcohol-exposed group made fewer reversals than the control group in visual discrimination reversal and exhibited more variability in extinction. These group differences remained significant after controlling for intellectual ability and conceptual set shifting. Variability in extinction and two measures of set shifting, perseverative errors on the Wisconsin Card Sorting Test and omission errors on reversal learning, were found to be robust predictors of parent-rated behavioral problems.

Neuroimaging findings in macrocephaly–capillary malformation: A longitudinal study of 17 patients

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.

Elements of morphology: standard terminology for the hands and feet

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 hands and feet and define and illustrate the terms that describe the major characteristics of the hands and feet. Published 2009 Wiley‐Liss, Inc.

Mutations in PIEZO2 Cause Gordon Syndrome, Marden-Walker Syndrome, and Distal Arthrogryposis Type 5

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fishers exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

Serum α-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia

An elevated risk of hepatoblastoma for children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia is well established. We describe five children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia for whom serial serum alpha-fetoprotein screening, usually in combination with abdominal ultrasound, led to early detection of hepatoblastoma.