WTX R353X mutation in a family with osteopathia striata and cranial sclerosis (OS-CS): case report and literature review of the disease clinical, genetic and radiological features

Osteopathia striata with cranial sclerosis (OS-CS; OMIM#300373) is a rare, X-linked dominant inherited skeletal dysplasia (prevalence 0.1/1 million people [1]), part of sclerosing bone dysplasias [2‐4], a group of disorders characterized by abnormally dense bones as a result of the prevalence of bone formation by osteoblasts over bone reabsorption by osteoclasts. Striated methaphyses were firstly described by Voorhoeve in 1924 [5]; thirty years later, Hurt [3] reported a case of association with cranial sclerosis. To date, about one hundred cases have been reported. Age at diagnosis and clinical presentation is highly variable, ranging from asymptomatic to neonatal lethal cases. Skull thickening, responsible for characteristic facies, and linear striations in the metaphyseal region of the long bones and pelvis represent disease main features, the latter representing a key feature for differential diagnosis [2‐4]. Nervous and internal organs defects can be associated. Causing-disease mutations of WTX (Wilms Tumor in the X; also called FAM123B and AMER1) have recently been identified.

The proband came to our attention at age 6 for evaluation of recurrent otitis media and bilateral hearing loss [6]. She was born at the 40th week of gestation after spontaneous vaginal delivery from unrelated, apparently healthy parents. Her weight at birth was 3.9 kg (>97th centile); no facial anomalies were noted. Her mother had previously had two male abortions and a healthy daughter (Figure 1). A skull X-ray, performed at age 3 because of high fever, right-eye and nasal bridge swelling, had shown dense basilar bones and decreased pneumatization of the mastoid and ethmoid cells [6]. Physical examination performed at age 6 showed narrow forehead with frontal bossing, hypertelorism with epicanthal folds, up-slanting palpebral fissures, wide depressed nasal bridge, mild macrocephaly (head circumference 53.8 cm, slightly >2SD), hypoplastic maxillae and delayed dentition, low-set ears (Figure 2a), and pectus excavatum. Inspection of the oral cavity revealed a high-arched palate and dental-position abnormalities. Otologic examination showed bilateral mild retraction of the tympanic membrane. The audiometric test revealed a severe mixed hearing loss with a wide gap in air conduction on the left side and medium-grade sensor neural hearing loss on the right side. High-resolution computed tomography (CT) of the temporal bone showed bilateral thickening and bone sclerosis of the skull base and mastoid cells with narrowing of the middle ear cavity, mastoid antrum, and eustachian canal, bilateral abnormal ossicular fixation to the bone surface of the middle ear cavity, and the presence of phlogistic tissue in the middle ear, confirmed by magnetic resonance [6]. X-rays of the skull and legs were performed because of clinical and CT findings suspicious for OS-CS, and revealed cranial vault’s sclerosis (more pronounced in frontal and parietal bones, and involving the orbits, sphenoid and petrous bones), and linear striations in the pelvis and metaphyseal region of long bones of lower and upper limbs (Figure 3a). Neurological examination excluded cranial nerves’ dysfunction and psychomotor delay. Cardiovascular and gastroenterological examinations were also normal.

Patient’s mother presented very similar facial features; particularly, she had mild hypertelorism with epicanthal folds, a slightly depressed nasal bridge and hypoplastic maxillae (Figure 2b). X-rays examination of lower limbs revealed longitudinal sclerotic striations in the metaphysis of femurs and tibias.

A systematic literature review was performed using PubMed database entering the words “osteopathia striata”, “cranial sclerosis”, “Horan-Beighton syndrome”, “WTX gene”. Articles written in English and published since 1953 were included (Additional file 1).

The clinical presentation is highly variable even within the same family. Patients can be asymptomatic and accidentally diagnosed during X-rays examinations, or present with disabling physical anomalies, sometimes leading to premature death. Age at diagnosis varies from neonatal period to the 5^th decade [9].

OS-CS has been classically considered an autosomal dominant condition with high penetrance and variable intra- and interfamilial expressivity [4, 9, 12, 15‐17, 21, 43] until the recent identification of mutated WTX (Wilms Tumor in the X; also called FAM123B and AMER1) within proximal Xq11.2 in affected families [8]. WTX can be spliced: the full length form encodes for a 1135 aminoacid protein, WTXs1, which possesses three binding sites for APC (adenomatous polyposis coli), a β-catenin- (C-terminal), a WT1- and a PIP2 (phosphatidylinositol 4.5 bisphosphate, at N-terminus)- binding site; and a shorter isoform, WTXs2 (missing aminoacids 50-326) keeps the first APC- binding domain [45‐47]. WTX interacts with AXIN1, APC and β-TrCP2, promoting the ubiquitination and proteasomal degradation of β-catenin (binding site located at the C-terminal) [48] and the inhibition of the WNT signaling pathway [45]. Both isoforms can bind β-catenin but, while WTXs1 has a predominant plasma membrane and cytoplasmic localization, WTXs2 (missing PIP2-binding site) is retained in the nucleus, suggesting the importance of cellular localization for protein function [8, 45, 47]. In absence of WTX, β-catenin accumulates in the nucleus and works as a transcriptional co-activator [31]. Because WNT signal pathway is involved in various embryonic development (including commitment of mesenchymal progenitor cells and differentiation of osteoblast precursors [49]) and homeostasis of adult tissues [50], its enhanced activity, due to mutations of the suppressor WTX, is responsible for the different alterations and phenotypes observed in patients.

Hemizygous males usually are more severely affected than heterozygous females and present, other than more marked bone sclerosis, craniofacial abnormalities, gross structural malformations of bones and internal organs, and significant pre- and postnatal lethality [20]. More recently, families with mildly affected males, characterized by longer longevity, mild short stature and neurodevelopmental disability, have been reported [18, 26, 35, 37, 43], although the phenotype has not been completely defined yet [20]. A genotype-phenotype correlation, where patient with 5′ WTX mutations were more severely affected than patients with 3′ WTX mutations was proposed by Jenkins [8], but not confirmed by Perdu [30, 31] who described mildly affected patients with 5′ WTX mutation, indicating a variable correlation between position of mutation and the severity of the phenotype. Because 5′ mutations produce a truncated, non-functioning protein, mild phenotype could be the result of a compensatory activity of WTXs2, even if the exact molecular mechanisms remain unidentified [20, 46].

Metaphyseal striations can be seen only in females, and males with mosaic mutations [18, 37, 40]. A reasonable explanation is the differential lionization of osteoblasts for which, similarly to what happens in heterozygous females presenting with random X chromosome inactivation patterns, only a certain amount of osteoblasts is affected [33].

Somatic mutations and deletions of WTX have been reported in 6 to 30% of patients with Wilms tumors (WT), a kidney cancer typical of childhood, arising from multipotent mesenchymal kidney precursors [7, 44, 46, 49]; WTX has later been identified as OS-CS disease-causing-gene, both in familial and sporadic cases. Despite germline mutations in tumor suppressor gene confer an elevated risk for cancer, and patients with WT and OS-CS share a similar distribution of WTX mutations, OS-CS is not associated with an increased neoplastic risk [51]. Moisan et al. [49] demonstrated in a conditional Wtx knockout mouse model the presence of malformations affecting organs derived from mesenchymal progenitors, including kidneys, adipose tissue, heart, spleen and bones, very similar to those reported in children with OS-CS. At the same time, some mice developed bilateral multifocal expansion of renal precursors, but not Wilms tumors, suggesting a complex role of WTX in kidney development, whose alteration can lead to tissue agenesis or overgrowth. Mutations associated to WTX-interacting proteins have also been advocated to explain tumor development [8].

Written informed consent was provided by parents on behalf of the patient for the publication of this case report and any accompanying images.