Multiple tumor types including leiomyoma and Wilms tumor in a patient with Gorlin syndrome due to 9q22.3 microdeletion encompassing the PTCH1 and FANC‐C loci

Abstract

Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant condition mainly characterized by the development of mandibular keratocysts which often have their onset during the second decade of life and/or multiple basal cell carcinoma (BCC) normally arising during the third decade. Cardiac and ovarian fibromas can be found. Patients with NBCCS develop the childhood brain malignancy medulloblastoma (now often called primitive neuro-ectodermal tumor [PNET]) in 5% of cases. The risk of other malignant neoplasms is not clearly increased, although lymphoma and meningioma can occur in this condition. Wilms tumor has been mentioned in the literature four times. We describe a patient with a 10.9 Mb 9q22.3 deletion spanning 9q22.2 through 9q31.1 that includes the entire codifying sequence of the gene PTCH1, with Wilms tumor, multiple neoplasms (lung, liver, mesenteric, gastric and renal leiomyomas, lung typical carcinoid tumor, adenomatoid tumor of the pleura) and a severe clinical presentation. We propose including leiomyomas among minor criteria of the NBCCS. 2894 INTRODUCTIONGorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS) also known as basal cell nevus syndrome (BCNS, OMIM #109400) is an autosomal dominant condition due to haploinsufficiency of PTCH1 and mainly characterized by the development of mandibular keratocysts which often have their onset during adolescence and/or multiple basal cell carcinomas normally arising after age 20 [Hahn et al., 1996;Evans and Farndon, 2002;Gorlin, 2004;Muzio et al., 2013]. Exonic, multiexonic, and whole-gene deletions have been reported in about 6% of individuals with NBCCS [Evans and Farndon, 2002]. The studies of disease prevalence come from the UK population, where it is nearer to 1:30,827 [Evans et al., 2010]; The actual figure could be higher still, since less severe cases may not be diagnosed and Jones et al. [2011] recently reported an incidence of 1 in 19,000 births.NBCCS is clinically diagnosed in patients with one major diagnostic criterion and molecular confirmation or two major criteria or one major and two minor diagnostic criteria [Bree et al., 2011]. The major criteria are the following: (1) BCC before the age of 20 or excessive numbers of BBCs out of proportion to prior sun exposure and skin type, (2) odontogenic jaw keratocyst prior to 20 years of age, (3) palmar or plantar pitting, (4) lamellar calcification of the falx cerebri, (5) medulloblastoma typically desmoplastic, and (6) first-degree relative with NBCCS. The minor criteria are the following: (1) rib anomalies, (2) other specific skeletal malformations and radiologic changes (i.e., vertebral anomalies, kyphoscoliosis, short fourth metacarpals, postaxial polydactyly), (3) macrocephaly, (4) cleft lip/palate, (5) ovarian/ cardiac fibromas, (6) lymphomesenteric cysts, and (7) ocular anomalies including the following: strabismus, hypertelorism, congenital cataract, glaucoma, coloboma.The typical facial phenotype includes macrocephaly, frontal bossing, coarse face ...

Diagnosis of 9q22.3 microdeletion syndrome in utero following identification of craniosynostosis, overgrowth, and skeletal anomalies

“…9q22.3 microdeletion syndrome manifests as Gorlin syndrome (GS), with metopic craniosynostosis, hydrocephalus, minor facial anomalies, and intellectual disability. GS is known to carry an increased risk for development of cancerous and non-cancerous tumors, specifically basal cell carcinoma, keratocystic odontogenic tumors, medulloblastoma, Wilms tumor, and cardiac or ovarian fibromas [Gorlin 2004;Garavelli et al, 2013]. Most cases of GS are caused by mutations in PTCH1, a tumor suppressor gene at 9q22.32 [Gorlin, 2004].…”

Gastric leiomyoma in a child with Gorlin–Goltz syndrome: First pediatric case

“…7 Garavelli et al recently confirmed an association between GGS and multiple leiomyomas (lung, liver, stomach, ovary, and kidney) in an adult with GGS due to a chromosome 9q22.3 deletion (which included PTCH1). 8 The authors suggested the inclusion of "fibromas and leiomyomas of other organs" in the minor criteria for the diagnosis of GGS. 8 The present pediatric case illustrates the need for this change to the diagnostic criteria to encompass the highly variable expressivity in GGS.…”

“…8 The authors suggested the inclusion of "fibromas and leiomyomas of other organs" in the minor criteria for the diagnosis of GGS. 8 The present pediatric case illustrates the need for this change to the diagnostic criteria to encompass the highly variable expressivity in GGS. Moreover, the possibility of a GIST or another malignant tumor of the gastrointestinal tract should always be taken into account, 5,9 and excluded solely on the basis of endoscopic/open biopsy and subsequent pathology.…”

Overgrowth Syndrome with 9q22.3 Microdeletion Detected by Microarray Comparative Genomic Hybridization

“…This syndrome is due to the mutation of PTCH1 and is characterized by clinical complications such as lamellar calcification of the falx cerebri, basal cell carcinoma, jaw keratocyst, and the palmar or plantar pits 5) . This syndrome is considered to be a precancerous condition for tumors such as medulloblastoma, Wilms' tumor, cardiac, and ovarian fibromas 5,10) . Our patient met only two minor criteria of BCNS 5,8) including macrocephaly and vertebral abnormalities.…”

“…Several cases with 9q22.3 microdeletion had Wilms' tumor and pelvic rhabdomyosarcoma 5) . Recently, a patient with BCNS syndrome due to 9q22.3 microdeletion which included the deletion of PTCH1 and the FANC-C loci presented with multiple tumors of leiomyoma and Wilms' tumor 10) . Deletion of PTCH1 and FANC-C loci were identified in our patient via CGH; however, the FANC-C loci deletion was not confirmed by FISH.…”