A novel WTX mutation in a female patient with osteopathia striata with cranial sclerosis and hepatoblastoma

Abstract

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant sclerosing bone dysplasia. Typically affected females show macrocephaly, characteristic facial appearance, cleft palate, mild learning difficulties, hearing loss, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis and scapulae. Typically affected males usually die at the fetal or early neonatal stage. Because of its variable expressivity, which ranges from asymptomatic to fetal death, clinical diagnosis of OSCS can be difficult. Here, we identify a unique female patient presenting with severe macrocephaly, characteristic facial appearance, developmental delay, and hepatoblastoma. Exome sequencing identified a novel de novo nonsense mutation (c.1045C>T, p.Glu349*) in the WTX gene associated with OSCS. The OSCS diagnosis was confirmed in this patient based on the hallmark appearance of longitudinal striations in long bones when viewed by X-ray. WTX is also known as a tumor suppressor gene, and somatic mutations in that gene have been identified in Wilms tumors. In addition to this patient, although two patients with OSCS have been reported to have colorectal cancer or ovarian cancer, Wilms tumor has never been reported in association with this disorder. Tumor susceptibility in patients with OSCS is discussed.

The genetic and epigenetic landscapes of hepatoblastomas

“…Three other HB exome sequencing studies [60][61][62] have been published. The first study on HBs was conducted by Eichenmuller et al [60], who investigated 15 samples of HB and three cases of an aggressive subtype of HB (HCC-like) that affects children over 5 years of age, and exhibits clinical and histopathological features that resemble hepatocellular carcinoma [63].…”

“…Fujita et al [61] reported a patient that had been with osteopathia striata, cranial sclerosis, and HB. A nonsense heterozygous mutation was identified in WTX (c.1045C > T p.Glu349), a tumor suppressor gene related to Wilm's tumor.…”

Mutational burden of hepatoblastomas: a role for the CX3CL1/CX3CR1 chemokine signaling pathway

“…Exome sequencing has broadened the understanding of the HB mutational profile [ [19], [27], [28], [29], [30]]. The commonalities disclosed by these studies, besides CTNNB1 mutations, were the low number of detectable somatic mutations, and pathogenic variants in genes from the WNT pathway, such as CAPRIN2 [27].…”

“…Clinically, overexpression of NQO1, a target gene of NFE2L2, was significantly associated with poor outcome, metastasis, vascular invasion, and the adverse prognostic C2 gene signature [26]. Other two exome analysis were based on syndromic patients who developed HB, including a boy with Simpson-Golabi-Behmel syndrome carrier of a germline GPC3 loss of function (LoF) mutation (29), and a girl presenting severe macrocephaly, facial dysmorphisms and developmental delay, in which a novel de novo germline nonsense mutation was detected in the WTX [30]. In a recent study [31], 16 HBs were included in a pan-cancer cohort of pediatric tumors, with the identification of CTNNB1 and TERT, genes already known to be frequently mutated in this type of tumor.…”

Novel AMER1 frameshift mutation in a girl with osteopathia striata with cranial sclerosis

“…Most of her clinical features are consistent with those reported in other individuals with the disorder. To our knowledge, around 30 pathogenic variants in AMER1 have previously been reported (Fujita et al 2014). AMER1 consists of 1135 amino acids.…”