Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations

Abstract

Oculoectodermal syndrome (OES) is a rare disease characterized by a combination of congenital scalp lesions and ocular dermoids, with additional manifestations including non-ossifying fibromas and giant cell granulomas of the jaw occurring during the first decade of life. To identify the genetic etiology of OES, we conducted whole-genome sequencing of several tissues in an affected individual. Comparison of DNA from a non-ossifying fibroma to blood-derived DNA allowed identification of a somatic missense alteration in KRAS NM_033360.3(KRAS):c.38G>A, resulting in p.Gly13Asp. This alteration was also observed in the patient's other affected tissues including the skin and muscle. Targeted sequencing in a second, unrelated OES patient identified an NM_033360.3(KRAS):c.57G>C, p.Leu19Phe alteration. Allelic frequencies fell below 40% in all tissues examined in both patients, suggesting that OES is a mosaic RAS-related disorder, or RASopathy. The characteristic findings in OES, including scalp lesions, ocular dermoids, and benign tumors, are found in other mosaic and germline RASopathies. This discovery also broadens our understanding of the spectrum of phenotypes resulting from KRAS alterations. Future research into disease progression with regard to malignancy risk and investigation of RAS-targeted therapies in OES is warranted. KRAS sequencing is clinically available and may also now improve OES diagnostic criteria.

Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies

“…Until recently, somatic cutaneous mosaicism was considered as a rare event with little or any clinical consequences. Recent genomic studies have recognized mutational somatic mosaicism in skin lesions with abnormal pigmentation, especially in those following the Blaschko lines (Amary et al, ; Groesser et al, ; Kurek et al, ; Peacock et al, ; Rivière et al, ; Shirley et al, ; Weinstein et al, ). The OES, ECCL, and SFMS syndromes are a group of oculocutaneous developmental mosaic RASopathies which exhibit common anomalies including focal scalp lesions, linear cutaneous hyperpigmentation, arachnoid cyst, and cardiac defects (Ardinger, Horii, & Begleiter, ; Ernst, Quinn, & Alawi, ; Moog, ).…”

“…The OES, ECCL, and SFMS syndromes are a group of oculocutaneous developmental mosaic RASopathies which exhibit common anomalies including focal scalp lesions, linear cutaneous hyperpigmentation, arachnoid cyst, and cardiac defects (Ardinger, Horii, & Begleiter, ; Ernst, Quinn, & Alawi, ; Moog, ). At the molecular level, these entities are caused by somatic mosaicism for mutations in genes encoding components of the RAS signaling pathway (Bennett et al, ; Boppudi et al, ; Groesser et al, ; Peacock et al, ). OES is a very rare disease characterized for a consistent combination of scalp lesions and epibulbar dermoids (Toriello, Lacassie, Droste, & Higgins, ).…”

“…The identification of somatic mutations in KRAS and FGFR1 genes in patients with cutaneous mosaic disorders could provide a tool for early diagnosis and surveillance of associated disorders. Non‐ossifying fibromas resulting in long bones stress fractures (Ardinger et al, ; Boppudi et al, ; Fickie & Stoler, ; Mermer, Kayhan, Karacelebi, & Percin, ; Peacock et al, ), giant cell granuloma of the mandibule and maxilla (Ardinger et al, ; Boppudi et al, ; Federici et al, ; Mermer et al, ; Peacock et al, ; Toriello et al, ), rhabdomyosarcoma (Ardinger et al, ), craniofacial, intracranial or intraspinal lipomas (Hunter, ), jaw osteomas (Zielinska‐Kazmierska, Grodecka, Jablonska‐Polakowska, & Arkuszewski, ), odontomas (Andreadis, Rizos, Belazi, Peneva, & Antoniades, ; Hauber, Warmuth‐Metz, Rose, Bröcker, & Hamm, ), ossifying fibromas (Moog et al, ), pilocytic‐low grade astrocytoma (Bieser et al, ; Brassesco et al, ; Valera et al, ), papillary glioneural tumor (Phi et al, ), dysembryoplastic neuroepithelial tumor (Bavle et al, ), and optic glioma (Kocak et al, ) can occur in these three oculocutaneous syndromes. In addition, malignant secondary tumors can arise from the nevi sebaceous in SFMS patients, including basal cell carcinoma and squamous carcinoma (Eisen & Michael; Idriss & Elston, ).…”

“…Three additional syndromes with overlapping clinical findings in eye, heart, skin, and hair have been recently shown to result from somatic mosaicism for mutations in the genes involved in the Ras pathway, including KRAS [OMIM *190070], HRAS [OMIM *190020], NRAS [OMIM *164790], and FGFR1 [OMIM *136350]. These entities are the oculoectodermal (OES, OMIM %600268) and Schimmelpenning‐Feuerstein‐Mims syndromes (SFMS, OMIM #163200), as well as encephalocraniocutaneous lipomatosis (ECCL, OMIM #613001), oculocutaneous disorders exhibiting pleiotropic anomalies that include scalp lesions, epilepsy, epibulbar dermoids, cloudy cornea, eyelid coloboma, coarctation of the aorta, and skin pigmentation abnormalities (Boppudi et al, ; Groesser et al, ; Kuroda et al, ; Peacock et al, ). Somatic mutations causing oculocutaneous mosaic RASopathies are recurrent and have been identified at KRAS codons 13, 19, and 146 in OES patients (4 subjects reported to date) (Boppudi et al, ; Peacock et al, ), KRAS codon 146 and FGFR1 codons 546 and 656 in ECCL (six reported patients) (Bennett et al, ; Boppudi et al, ), and HRAS codon 13 (2 patients), KRAS codon 12 (3 subjects), and NRAS codon 61 (1 subject) in individuals with a SFMS diagnosis (Groesser et al, ; Igawa et al, ; Kuroda et al, ; Lihua, Feng, Shanshan, Jialu, & Kewen, ; Sun et al, ; Wang, Qian, Zhang, & Zhou, ).…”

“…These entities are the oculoectodermal (OES, OMIM %600268) and Schimmelpenning‐Feuerstein‐Mims syndromes (SFMS, OMIM #163200), as well as encephalocraniocutaneous lipomatosis (ECCL, OMIM #613001), oculocutaneous disorders exhibiting pleiotropic anomalies that include scalp lesions, epilepsy, epibulbar dermoids, cloudy cornea, eyelid coloboma, coarctation of the aorta, and skin pigmentation abnormalities (Boppudi et al, ; Groesser et al, ; Kuroda et al, ; Peacock et al, ). Somatic mutations causing oculocutaneous mosaic RASopathies are recurrent and have been identified at KRAS codons 13, 19, and 146 in OES patients (4 subjects reported to date) (Boppudi et al, ; Peacock et al, ), KRAS codon 146 and FGFR1 codons 546 and 656 in ECCL (six reported patients) (Bennett et al, ; Boppudi et al, ), and HRAS codon 13 (2 patients), KRAS codon 12 (3 subjects), and NRAS codon 61 (1 subject) in individuals with a SFMS diagnosis (Groesser et al, ; Igawa et al, ; Kuroda et al, ; Lihua, Feng, Shanshan, Jialu, & Kewen, ; Sun et al, ; Wang, Qian, Zhang, & Zhou, ). Such pathogenic mutations also confer an elevated risk for developing a variety of tumors commonly associated with these oculocutaneos disorders (Aslan et al, ; Eisen & Michael; ; Kocak, Yarar, & Carman, ; Moog, ; Peacock et al, ; Toriello et al, ; Valera et al, ).…”