Dataset Information

Primrose syndrome: Characterization of the phenotype in 42 patients.

ABSTRACT: Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.

SUBMITTER: Melis D

PROVIDER: S-EPMC7384157 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Primrose syndrome: Characterization of the phenotype in 42 patients.

Melis Daniela D Carvalho Daniel D Barbaro-Dieber Tina T Espay Alberto J AJ Gambello Michael J MJ Gener Blanca B Gerkes Erica E Hitzert Marrit M MM Hove Hanne B HB Jansen Sandra S Jira Petr E PE Lachlan Katherine K Menke Leonie A LA Narayanan Vinodh V Ortiz Damara D Overwater Eline E Posmyk Renata R Ramsey Keri K Rossi Alessandro A Sandoval Renata Lazari RL Stumpel Constance C Stuurman Kyra E KE Cordeddu Viviana V Turnpenny Peter P Strisciuglio Pietro P Tartaglia Marco M Unger Sheela S Waters Todd T Turnbull Clare C Hennekam Raoul C RC

Clinical genetics 20200420 6

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize t ...[more]

PMID: 32266967

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Project description:IntroductionPhelan-McDermid syndrome (PMS) is a genetic disorder caused by the loss of the terminal region of chromosome 22 or by pathogenic or likely-pathogenic variants in SHANK3 gene. Individuals with PMS are affected by a variable degree of intellectual disability, delay or absence of speech, low muscle tone, motor delay epilepsy, and autistic features. We have performed an observational trial aimed to psychometrically characterize individuals carrying deletions or pathogenic variants in SHANK3, to eventually build a foundation for a subsequent precision psychiatry clinical trial with vafidemstat, a LSD1 inhibitor in Phase II clinical development.MethodsWe have conducted a pilot study to clinically characterize the profile of 30 subjects, all diagnosed of molecularly confirmed PMS. Subjects were phenotypically characterized by applying different psychometric scales, including Repetitive Behavior Questionnaire (RBQ), Vineland Adaptive Behavior Scales, ADOS-2, the Battelle developmental inventory screening test and the Behavior Problems Inventory (BPI). Nineteen patients were included in the pilot study, followed by additional 11 individuals in the validation set.ResultsUnsupervised hierarchical clustering of the collected psychometric data identifies three groups of patients, with different cognitive and behavioral profile scores. Statistically significant differences in deletion sizes were detected comparing the three clusters (corrected by gender), and the size of the deletion appears to be positively correlated with ADOS and negatively correlated with Vineland-A and -C scores. No correlation was detected between deletion size and the BPI and RBQ scores.DiscussionThis analysis presents new data on the best potential endpoints, for a future clinical study exploring vafidemstat actionability for SHANK3-associated psychiatric disorders, constituting a good example of how Precision Medicine may open new avenues to understand and treat Central Nervous System (CNS) disorders, pioneering individual management in PMS.

Project description:BackgroundPhelan-McDermid syndrome (PMS) is a neurodevelopmental disorder associated with a terminal deletion affecting chromosome 22 (22q13) that results in the loss of function of the SHANK3 gene. SHANK3 has also been identified in gene-linkage studies to be associated with autism spectrum disorder (ASD). Diagnosis of ASD in individuals with PMS is complicated by the presence of moderate to profound global developmental delay/intellectual disability as well as other co-morbid systemic and neurological symptoms.MethodsThe current study aimed to characterize the symptoms of ASD in patients with PMS and to do a preliminary exploration of genotype-ASD phenotype correlations. We conducted a standardized interview with 40 parents/guardians of children with PMS. Further, we conducted analyses on the relationship between disruption of SHANK3 and adjacent genes on specific characteristic symptoms of ASD in PMS in small subset of the sample.ResultsThe majority of PMS participants in our sample displayed persistent deficits in Social communication, but only half met diagnostic criteria under the restricted, repetitive patterns of behavior, interests, or activities domain. Furthermore, logistic regressions indicated that general developmental delay significantly contributed to the ASD diagnosis. The analyses relating the PMS genotype to the behavioral phenotype revealed additional complex relationships with contributions of genes in both deleted and preserved SHANK3 regions to the ASD phenotype and other neurobehavioral impairments.ConclusionsThere appears to be a unique behavioral phenotype associated with ASD in individuals with PMS. There also appears to be contributions of genes in both deleted and preserved SHANK3 regions to the ASD phenotype and other neurobehavioral impairments. Better characterization of the behavioral phenotype using additional standardized assessments and further analyses exploring the relationship between the PMS genotype and behavioral phenotype in a larger sample are warranted.

Dataset Information

Primrose syndrome: Characterization of the phenotype in 42 patients.

Publications

Primrose syndrome: Characterization of the phenotype in 42 patients.

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