A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

Kamien, Benjamin; Ronan, Anne; Poke, Gemma; Sinnerbrink, Ingrid B.; Baynam, Gareth; Ward, Michelle C.; Gibson, William T.; Dudding‐Byth, Tracy; Scott, Rodney J.

doi:10.1159/000484532

Cited by 44 publications

(44 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, there has been an effort to classify these syndromes based on similar overgrowth symptoms, leading to an effort to find the causative gene for each disease group. Through conventional genetic evaluations, germline variants were identified first, such as NF1 for neurofibromatosis and NSD1 for Sotos syndrome [20].…”

Section: Discussionmentioning

confidence: 99%

Detailed analysis of phenotypes and genotypes in megalencephaly-capillary malformation-polymicrogyria syndrome caused by somatic mosaicism of PIK3CA mutations

Park

Shin

Yoo

et al. 2020

Orphanet J Rare Dis

View full text Add to dashboard Cite

Background: Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) belongs to a group of conditions called the PIK3CA-related overgrowth spectrum (PROS). The varying phenotypes and low frequencies of each somatic mosaic variant make confirmative diagnosis difficult. We present 12 patients who were diagnosed clinically and genetically with MCAP. Genomic DNA was extracted mainly from the skin of affected lesions, also from peripheral blood leukocytes and buccal epithelial cells, and target panel sequencing using high-depth nextgeneration sequencing technology was performed. Results: Macrocephaly was present in 11/12 patients (92%). All patients had normal body asymmetry. Cutaneous vascular malformation was found in 10/12 patients (83%). Megalencephaly or hemimegalencephaly was noted in all 11 patients who underwent brain magnetic resonance imaging. Arnold-Chiari type I malformation was also seen in 10 patients. Every patient was identified as having pathogenic or likely pathogenic variants of the PIK3CA gene. The variant allele frequency (VAF) ranged from 6.3 to 35.3%, however, there was no direct correlation between VAF and the severity of associated anomalies. c.2740G > A (p.Gly914Arg) was most commonly found, in four patients (33%). No malignancies developed during follow-up periods. Conclusions: This is the first and largest cohort of molecularly diagnosed patients with MCAP in Korea. Targeted therapy with a PI3K-specific inhibitor, alpelisib, has shown successful outcomes in patients with PROS in a pilot clinical study, so early diagnosis for genetic counseling and timely introduction of emerging treatments might be achieved in the future through optimal genetic testing.

show abstract

Section: Discussionmentioning

confidence: 99%

Detailed analysis of phenotypes and genotypes in megalencephaly-capillary malformation-polymicrogyria syndrome caused by somatic mosaicism of PIK3CA mutations

Park

Shin

Yoo

et al. 2020

Orphanet J Rare Dis

View full text Add to dashboard Cite

show abstract

“…While calves in this scenario may be relatively large to the dam, they may not be oversized in absolute terms of population normals. In the human literature neonates that are large of for gestational age are typically above 97 th percentile for birth weight at delivery, although the definition varies slightly by condition 77 . Mechanistically syndromes of overgrowth may be due to increased numbers of cells, hypertrophy, increases in the interstitium (such as fluid accumulation) or a combination of these conditions 77 .…”

Section: Spontaneous Losmentioning

confidence: 99%

Overgrowth Syndrome

Donnelly

Rivera

2019

Veterinary Clinics of North America: Food Animal Practice

View full text Add to dashboard Cite

“…Congenital overgrowth disorders are characterized by accelerated growth, variable intellectual disability, and susceptibility for neoplasia (Cohen, 1998;Edmondson & Kalish, 2015;Kamien et al, 2018;Verge & Mowat, 2010). Most overgrowth syndromes are associated with alterations in molecular pathways that control cell growth.…”

Section: Introductionmentioning

confidence: 99%

Tatton‐Brown‐Rahman syndrome: Six individuals with novel features

Balci

Strong

Kalish

et al. 2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Tatton‐Brown Rahman syndrome (TBRS) is an overgrowth‐intellectual disability syndrome caused by heterozygous variants in DNMT3A. Seventy‐eight individuals have been reported with a consistent phenotype of somatic overgrowth, mild to moderate intellectual disability, and similar dysmorphisms. We present six individuals with TBRS, including the youngest individual thus far reported, first individual to be diagnosed with tumor testing and two individuals with variants at the Arg882 domain, bringing the total number of reported cases to 82. Patients reported herein have additional clinical features not previously reported in TBRS. One patient had congenital diaphragmatic hernia. One patient carrying the recurrent p.Arg882His DNMT3A variant, who was previously reported as having a phenotype due to a truncating variant in the CLTC gene, developed a ganglioneuroblastoma at 18 months and T‐cell lymphoblastic lymphoma at 6 years of age. Four patients manifested symptoms suggestive of autonomic dysfunction, including central sleep apnea, postural orthostatic hypotension, and episodic vasomotor instability in the extremities. We discuss the molecular and clinical findings in our patients with TBRS in context of existing literature.

show abstract

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

Cited by 44 publications

References 101 publications

Detailed analysis of phenotypes and genotypes in megalencephaly-capillary malformation-polymicrogyria syndrome caused by somatic mosaicism of PIK3CA mutations

Detailed analysis of phenotypes and genotypes in megalencephaly-capillary malformation-polymicrogyria syndrome caused by somatic mosaicism of PIK3CA mutations

Overgrowth Syndrome

Tatton‐Brown‐Rahman syndrome: Six individuals with novel features

Contact Info

Product

Resources

About