Clinical management of patients with ASXL1 mutations and Bohring–Opitz syndrome, emphasizing the need for Wilms tumor surveillance

Abstract

Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.

Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma

“…Bohring-Opitz syndrome ( BOS) is a rare genetic syndrome characterized by severe growth and feeding problems, severe developmental delay/intellectual disability, typical facial appearance (trigonocephaly, retrognathia, prominent eyes with underdeveloped supraorbital ridges, upslanting palpebral fissures, depressed nasal bridge, anteverted nares, low-set and posteriorly-rotated ears, glabellar nevus flammeus, low anterior hairline), microcephaly, forehead hirsutism, cleft lip and palate, retinal abnormalities, flexion anomalies of upper limbs with radial head dislocation and ulnar deviation of fingers (“BOS posture”), lower limb anomalies, structural brain anomalies, and seizures (9–14). About 40% of patients die in early childhood, typically from unexplained bradycardia, obstructive apnea, or pulmonary infections.…”

The Role of Additional Sex Combs-Like Proteins in Cancer

“…Given that only ~50 patients with BOS have been described and that BOS patients frequently die as infants, cancer risk associated with this syndrome is not well defined. However, BOS syndrome patients have been reported to have nephroblastomatosis, meduloblastoma, and Wilms tumor, suggesting that germline ASXL1/3 mutations could increase the risk for cancer predisposition (Russell et al 2015). …”

A novel de-novo frameshift mutation of the ASXL1 gene in a classic case of Bohring–Opitz syndrome

“…Since the initial description of the Bohring-Opitz syndrome as a rare but distinct entity from the C syndrome/ Opitz trigonocephaly syndrome by Dr Axel Bohring in 1999, only 52 cases worldwide have been described in the peer-reviewed literature (Dangiolo et al, 2015;Russell et al, 2015). The majority of these cases were considered to have Bohring-Opitz syndrome (BOPS) as they fulfilled the clinical diagnostic criteria established by Hastings et al (2011); however, only a minority have a confirmed molecular diagnosis to date.…”