Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin.
The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype–phenotype correlations and phenotypic variability have yet to be fully clarified.
Methods
We report genotype–phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported.
Results
The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations.
Conclusions
In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.
Background Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in KANSL1 . It was mainly described in children. Methods A retrospective study on 9 subjects aged 19–45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood. Results Seven patients had a 17q21.31 deletion and two a point mutation in KANSL1 . All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited. Conclusions Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures.
Pitt-Hopkins syndrome (PTHS) is an emerging condition characterized by severe intellectual disability (ID), typical facial gestalt, and additional features, such as breathing abnormalities. Because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly, large mouth, and constipation, differential diagnosis of PTHS with respect to Angelman, Rett, and Mowat-Wilson syndromes represents a relevant clinical issue, and many patients are currently undergoing genetic tests for different conditions that are assumed to fall within the PTHS clinical spectrum. During a search for TCF4 mutations in 78 patients with a suspected PTHS, haploinsufficiency of TCF4 was identified in 18. By evaluating clinical features of patients with a proven TCF4 mutation with those of patients without, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combination of the following characteristics: ID with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing abnormalities, motor incoordination, ocular anomalies, constipation, seizures, typical behavior, and subtle brain abnormalities. On the basis of these observations, here we propose a clinically based score system as useful tool for driving a first choice molecular test for PTHS. This scoring system is also proposed for a clinically based diagnosis of PTHS in absence of a proven TCF4 mutation.
In the author information for "CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases" published in Am J Med Genet Part A 164: 2557–2566, contributors Elaine Zackai, Margaret Harr, Elizabeth Bhoj, Avni Santani, Rebecca Ganetzky, and Donna M. McDonald-McGinn were incorrectly affiliated with the Division of Craniofacial Medicine, Seattle Children's Hospital, Seattle, Washington. Please note that for these six authors the correct affiliation should be the Children's Hospital of Philadelphia, Division of Human Genetics and Molecular Biology, Philadelphia, Pennsylvania. The correct author information listing should read: Tara L. Wenger,1 Margaret Harr,2 Stefania Ricciardi,3 Elizabeth Bhoj,2 Avni Santani,2 Margaret P. Adam,4 Sarah S. Barnett,5 Rebecca Ganetzky,2 Donna M. McDonald-McGinn,2 Domenica Battaglia,6 Stefania Bigoni,7 Angelo Selicorni,8 Giovanni Sorge,9 Matteo Della Monica,10 Francesca Mari,11 Elena Andreucci,12 Silvia Romano,13 Guido Cocchi,14 Salvatore Savasta,15 Baris Malbora,16 Giuseppe Marangi,3 Livia Garavelli,17 Marcella Zollino,3 Elaine H. Zackai2 1Division of Craniofacial Medicine, Seattle Children's Hospital, Seattle, WA 2Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia, Philadelphia, PA 19104 3Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy 4Division of Genetic Medicine, University of Washington School of Medicine, Seattle, WA 5Division of Genetics, University of Missouri Children's Hospital 6UOC di Neuropsichiatria Infantile, Universitá Cattolica del Sacro Cuore, Roma, Italy 7Unitá di Genetica Medica, Azienda Ospedaliero-Universitaria di Ferrara, Italy 8Dipartimento di Pediatria, Ospedale S. Gerardo/Fondazione MBBM, Universitá di Milano-Bicocca, Monza, Italy 9Unità Operativa Complessa di Clinica Pediatrica, Dipartimento di Scienze Mediche e Pediatriche, Azienda Ospedaliera Universitaria "Policlinico - Vittorio Emanuele", Università di Catania, Catania, Italy 10Unità Operativa di Genetica Medica, Ospedale Gaetano Rummo, Benevento, Italy 11UOC di Genetica Medica, Universitá di Siena, Siena, Italy 12Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy 13Unitá di Genetica Medica, Dipartimento di Fisiopatologia Clinica, Azienda Ospedaliero Universitaria "A. Meyer", Universitá di Firenze, Italy 14UO di neonatologia, Policlinico S. Orsola-Malpighi, Università di Bologna, Bologna, Italy 15Dipartimento di Pediatria, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 16Department of Pediatrics, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul, Turkey 17Unitá di Genetica Clinica, Dipartimento Ostetrico-Ginecologico e Pediatrico, Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale S Maria Nuova, Reggio Emilia, Italy The Publisher regrets the errors.
Summary Objective Seizure disorder is one of the most relevant clinical manifestations in Wolf‐Hirschhorn syndrome ( WHS ) and it acts as independent prognostic factor for the severity of intellectual disability (ID) . LETM 1 , encoding a mitochondrial protein playing a role in K + /H + exchange and in Ca 2+ homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM 1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside. Methods Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array‐comparative genomic hybridization (a‐CGH). Real‐time polymerase chain reaction (RT‐PCR) on messanger RNA (mRNA) of LETM1 and CPLX1 . Direct sequencing of LETM1 . Results Three unusual 4p16.3 deletions were detected by array‐ CGH in absence of a obvious clinical diagnosis of WHS . Two of these, encompassing LETM 1 , were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM 1 , and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM 1 had seizures, whereas seven of seven with interstitial deletions including LETM 1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM 1 . Significance We consider that haploinsufficiency not limited to LETM 1 but including other genes acts as a risk factor for the WHS ‐associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes reside in the terminal 1.5 Mb region on 4p, most likely distal to LETM 1 . A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .
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