The male phenotype in osteopathia striata congenita with cranial sclerosis

Abstract

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked disease caused by truncating mutations in WTX. Females exhibit sclerotic striations on the long bones, cranial sclerosis, and craniofacial dysmorphism. Males with OSCS have significant skeletal sclerosis, do not have striations but do display a more severe phenotype commonly associated with gross structural malformations, patterning defects, and significant pre- and postnatal lethality. The recent description of mutations in WTX underlying OSCS has led to the identification of a milder, survivable phenotype in males. Individuals with this presentation can have, in addition to skeletal sclerosis, Hirschsprung disease, joint contractures, cardiomyopathy, and neuromuscular anomalies. A diagnosis of OSCS should be considered in males with macrocephaly, skeletal sclerosis that is most marked in the cranium and the absence of metaphyseal striations. The observation of striations in males may be indicative of a WTX mutation in a mosaic state supporting the contention that this sign in females is indicative of the differential lyonization of cells in the osteoblastic lineage.

Prenatal Diagnosis of Osteopathia Striata with Cranial Sclerosis in a Male Fetus with a ~330kb Deletion of Xq11.1 Involving the WTX Gene

“…The use of various molecular and cytogenetic techniques allowed for the diagnosis of the condition in her affected sons and her low level mosaicism. To our knowledge, it also represents the second case of documented WTX mosaicism and the first in a female [2].…”

“…The hemizygous male phenotype is often more severe than what is seen in females. It consists of significant skeletal sclerosis, absent metaphyseal striations, macrocephaly, facial dysmorphisms, micrognathia, prominent lumbar lordosis, joint luxaation, camptodactyly, flexion contractures, omphalocele, duodenal web, gut malrotation, inguinal hernia, Hirschsprung disease, patent ductus arteriosus, atrial and ventricular septal defects, left ventricular non-compaction, tricuspid insufficiency, and multicystic kidneys [2]. Within and among families there can be a variable range of penetrance and phenotypic expression regardless of the WTX mutation.…”

“…It also promotes the ubiquitylation and degradation of β-catenin. Both WTX isoforms are able to bind β-catenin [2,4,5,6].…”

“…However, recent studies have shown that this is not always the case. Three males, two of whom survived into adulthood, with mutations in the 5΄ region of WTX had a mild phenotype calling into question the relationship between the location of the WTX mutation and its resulting phenotype [2,5]. Non-mosaic males that possess a WTX mutation 3΄ to the acidic domain and those who are mosaic for a WTX deletion have a milder phenotype [7].…”

“…For males, OSCS causes fetal or neonatal death. Males that do survive have the features of females with OSCS along with hyperostosis, cardiac, intestinal and genitourinary malformations [2,3]. Other features of OSCS may include: clubfoot; small ventricular septal defects, aortic stenosis; clinodactyly; dental and visual problems; hydrocephalus; hypertelorism, flat nasal bridge; scoliosis of the back; long fingers, facial nerve palsy; and mild mental retardation.…”