Extending the phenotype of BMPER-related skeletal dysplasias to ischiospinal dysostosis

Patient 1 was a 2-year-old girl, a second child born to a healthy non-consanguineous Swedish couple after an uncomplicated pregnancy. The older brother was healthy. The patient was born in week 41+0 after an uncomplicated delivery with BW 2590 g (z = −1.9), BL 46 cm (z = −1.9), OFC 33 cm (z =−1.0). The neonatal period and psychomotor development were unremarkable. At age 14 months, she had short stature with short trunk, hypoplastic thorax, protruding abdomen, and mild facial dysmorphism. Extremities were normal. At age two years her height was 76.2 cm (z = −3.3), she had hearing loss, mechanism of which is still under investigation, delayed speech development, and wheezing upon cold exposure and physical exercise. Repeated renal ultrasonography did not show nephrogenic rests or cysts, but will continue until age 7 years.

Patient 2 was a 19-year-old male, a second child of a healthy non-consanguineous Korean couple. He was born after an uncomplicated full-term pregnancy with BW 3190 g (z = −0.43), BL 46 cm (z = −1.42), and OFC 35 cm (z = 0.20). Respiratory distress immediately after birth required oxygen therapy. Abdominal distension, hydronephrosis and urethral stricture were noted during the neonatal period, but neither nephrogenic rests nor cysts. He showed mild facial dysmorphic features, a short trunk and pectus carinatum. At age three months, he required brief mechanical ventilation due to pneumonia and suffered from seasonal asthma attacks thereafter. Lack of urination control required intermittent catheterization from two years of age. He suffered from fecal incontinence and impaction. He stood with assistance and spoke only single words at age two years. Progressive right pes equinus deformity developed along with deterioration of lower extremity motor function, which limited outdoor ambulation to about five minutes at age 19 years. Untethering of the spical cord was considered but the patient was not compliant. His height was 143 cm (z = −5.67) and weight 27.6 kg (z = −9.23), and his school performance is normal. The radiographic phenotypes are summarized in Figs. 2 and 3 and clinical characteristics in Additional file 1: Table S1.

For patient 1, whole exome, subsequent Sanger sequencing and segregation analysis of the family revealed compound heterozygous mutations in the BMPER: NM_133468_4:c.[416C>G];[942G>A], p.[Thr139Arg];[Trp314*] (Fig. 3a). The amino acid substituted by the missense mutation is highly conserved among species (Fig. 3b). For patient 2, Sanger sequencing of the BMPER showed three sequence variants: NM_133468_4: c.[1672C>T;1988G>A];[c.1672C>T], p.[Arg588*;Cys662Tyr];[Arg588*]. The two variants on the same allele were inherited from the mother and the single mutation from the father (Fig. 3a). The variant NM_133468.4:c.1988G>A; p.Cys663Tyr is rare and predicted to be pathogenic (Table 1), but as the truncating mutation p.Arg558* is located upstream, p.Cys663Tyr substitution is most probably not involved in pathogenesis of this patient’s ISD.

Previous reports ascertained biallelic BMPER mutations in six patients with DSD [9, 13] and three siblings with attenuated DSD [12]. In this report we show that ISD a disorder phenotypically similar, but much milder, than DSD is also caused by biallelic mutations in the BMPER gene.

The BMPER encodes a 658 amino acid protein, which regulates organogenesis through the BMP signaling pathway. It is highly expressed in lungs, brain and chondrocytes. The knockout mice for the Bmp-binding protein crossveinless 2 (Bmper) show defects of vertebral and cartilage development, renal hypoplasia, as well as abnormal lung alveoli [14]. The knockout mouse phenotype is recapitulated by the manifestations in patients with BMPER mutations. The most prominent features are vertebral segmentation anomalies and kidney abnormalities [2‐4, 7‐9, 11]. Kidney abnormalities (cysts and nephroblastomatosis) have been reported in most patients with DSD [7‐11], but only in some patients with ISD [3, 4]. Patient 2 has hydronephrosis due to neurogenic bladder. However, neither renal cysts nor nephroblastomatosis were present in our patients. Our observation indicates that kidney abnormalities are not necessarily a feature in mildly affected patients with BMPER mutations.

Patient 1 is compound heterozygous for a missense variant p.Thr139Arg and for a nonsense mutation p.Trp314*, which could explain her milder phenotype. Patient 2 is homozygous for the nonsense mutation p.Arg558*, which is predicted to result in a stop codon in the von-Willebrand factor D domain and loss of Trypsin-inhibitor like domain (Fig. 1a). With the available data, it is impossible to predict which mutations cause DSD and which cause ISD. It may be that some nonsense mutations undergo nonsense-mediated mRNA decay, while others do not and that the latter may retain some residual function. Also, other genetic factors might modify the clinical phenotype. Further molecular studies are needed to elucidate the molecular impact of the different mutations in BMPER.

In conclusion, our report extends the phenotypic variabilities in BMPER-related skeletal disorders. This dysostosis family encompasses phenotypes from mild ISD to lethal DSD.