Prenatal and postnatal findings in serpentine fibula polycystic kidney syndrome and a review of the NOTCH2 spectrum disorders

Abstract

Serpentine fibula polycystic kidney syndrome (SFPKS; OMIM600330) is a rare skeletal dysplasia with a characteristic phenotype that includes polycystic kidneys, S-shaped fibulas, and abnormal craniofacial features. SFPKS shares features with Alagille (AGS; OMIM) and Hajdu-Cheney (HCS; OMIM10250) syndromes. All three syndromes result from mutations in the gene that encodes NOTCH2, one of the receptors involved in Notch signaling. Notch signaling is a major developmental signaling pathway, as well as a key regulator of numerous cellular processes. In this report, we present the prenatal ultrasound and postnatal findings in a 23-week fetus with severe manifestations of SPKS and heterozygosity for a de novo mutation in exon 34 of NOTCH2. These findings expand the phenotypic spectrum of NOTCH2 mutations and demonstrate the findings in the prenatal period.

Dental implications in Hajdu–Cheney syndrome: A novel case report and review of the literature

“…Furthermore, different clinical manifestations have been shown within a family (Han et al., ). Therefore, HCS and PFPKS are single disease entity with a wide phenotypic spectrum (Gray et al., ; Martin et al., ). In contrast to the HCS mutations, AS is caused by haploinsufficient mutations (missense mutations and early translation termination mutations not located in the last exon) resulting in a weak NOTCH2 signaling effect.…”

Novel phenotypic feature in a patient with a recurrent NOTCH2 nonsense mutation

“…It is the most distal disease‐causing variant documented for the 2471‐amino acid protein. The variant has been reported previously in five patients with HJCYS (Dillon et al, 2018; Isidor et al, 2011; Martin et al, 2014; Regev et al, 2019; Simpson et al, 2011; Stark et al, 2017; Zhu et al, 2015) and two with SFPKS (Isidor et al, 2011; Martin et al, 2014). An additional entry from Israel (VCV000518450.1) associated with a patient with HJCYS is also documented in the ClinVar database.…”

“…The seven cases of HJCYS/SFPKS with the R2400X nonsense codon were at different ages when they were clinically assessed, ranging from infancy to middle‐aged adulthood. One was identified through prenatal testing and the pregnancy was terminated at 23 weeks (Martin et al, 2014). One patient was reported to have intestinal obstruction and malrotation which required laparotomy without colectomy (Regev et al, 2019), while another had multiple bowel obstructions requiring laparotomy (Zhu et al, 2015), but imperforate anus was not reported as a phenotype in any of the patients.…”

Mechanistic and therapeutic insights gained from studying rare skeletal diseases

“…Serpentine fibula-polycystic kidney syndrome, thought to be a filamin-related disorder based on clinical and radiographic phenotype, clearly illustrates this concept. However serpentine fibula-polycystic kidney syndrome and the rare Hajdu-Cheney syndrome are caused by truncating mutations in neurogenic locus notch homolog 2 (NOTCH2) [6]. This raises the interesting hypothesis of filamin involvement in the NOTCH signaling pathway.…”