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

Abstract

Osteopathia striata with cranial sclerosis (OSCS) is a rare X-linked dominant genetic disorder resulting mutation in the WTX gene. Clinically, OSCS presents with linear striations in the metaphyseal region of the long bones and pelvis in combination with sclerosis of the cranium and face. A twenty-seven year old G5T1P3A0L2 woman with a history of peri-and neonatal infant male deaths was referred to us at 22 weeks, 6 days into her recent pregnancy. Ultrasound evaluation identified a male fetus, bilaterally enlarged lateral ventricles, a cloverleaf skull, suspected bilateral cleft lip, nuchal thickening, bilateral bowed radii and ulnae, gastroschisis with herniated viscera, bilateral absent fibula and clubfeet. The results of prenatal testing identified a male fetus with a 330kb Xq11.1 deletion involving the entire WTX gene. Initial microarray analysis of maternal blood identified a normal female karyotype, 46,XX. FISH analysis with a BAC clone mapped to the WTX gene identified low-level mosaicism in blood and buccal samples, 17% and 15%, respectively, which explained the negative maternal microarray result.

The phenotypic spectrum of AMER1‐related osteopathia striata with cranial sclerosis: The first Canadian cohort

“…OSCS is traditionally considered to be a skeletal dysplasia and remains in the nosology and classification of skeletal disorders (Mortier et al, 2019). As a result, many publications regarding OSCS have focused on the skeletal findings associated with OSCS (Jenkins et al, 2009; Lazar et al, 1999; Perdu et al, 2010; Tomita et al, 2019; Wilson et al, 2013). Case reports and emerging literature have emphasized other nonskeletal manifestations of OSCS.…”

Mosaic Deletions of Known Genes Explain Skeletal Dysplasias With High and Low Bone Mass

“…(12) The presence of a high percentage of cells harboring the AMER1 deletion in the bone tissue of the patient could potentially explain why she is affected by OSCS despite having a relatively low level of mosaicism in the blood comparable to the unaffected subject reported by Wilson and colleagues. (12) Patient 2 had characteristic features of CCD, but the delay of bone mineralization was much more severe than typically seen in CCD, and the phenotype initially resembled hypophos-phatasia. The patient also had decreased levels of alkaline phosphatase and markedly reduced BMD.…”

“…( 12 ) The presence of a high percentage of cells harboring the AMER1 deletion in the bone tissue of the patient could potentially explain why she is affected by OSCS despite having a relatively low level of mosaicism in the blood comparable to the unaffected subject reported by Wilson and colleagues. ( 12 )…”

“…(8) Somatic mosaicism of AMER1 mutations has been reported in male patients with OSCS (8)(9)(10)(11) and in one asymptomatic mother of OSCS patients. (12) Germline mosaicism has also been reported. (13) Cleidocranial dysplasia (CCD, OMIM: 119600) is an autosomal dominant skeletal disorder characterized by absent or hypoplastic clavicles, dental anomalies, and delayed closure of fontanelles.…”

“…( 8 ) Somatic mosaicism of AMER1 mutations has been reported in male patients with OSCS ( 8–11 ) and in one asymptomatic mother of OSCS patients. ( 12 ) Germline mosaicism has also been reported. ( 13 )…”