Alternative titles; symbols
SNOMEDCT: 721975004; ORPHA: 1824;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q14.2 | Lowry-Wood syndrome | 226960 | Autosomal recessive | 3 | RNU4ATAC | 601428 |
A number sign (#) is used with this entry because of evidence that Lowry-Wood syndrome (LWS) is caused by homozygous or compound heterozygous mutation in the RNU4ATAC gene (601428), encoding a small nuclear RNA (snRNA) component of the U12 (RNU12; 620204)-dependent (minor) spliceosome, on chromosome 2q14.
Lowry-Wood syndrome (LWS) is characterized by multiple epiphyseal dysplasia and microcephaly. Patients exhibit intrauterine growth retardation and short stature, as well as developmental delay and intellectual disability. Retinal degeneration has been reported in some patients (Farach et al., 2018; Shelihan et al., 2018).
Microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) and Roifman syndrome (RFMN; 616651), the features of which overlap with those of Lowry-Wood syndrome, are also caused by biallelic mutation in the RNU4ATAC gene.
Lowry and Wood (1975) described epiphyseal dysplasia, microcephaly, and nystagmus in 2 brothers. The radiologic finding consisted of small and irregular epiphyses, square iliac bones, and flattened acetabula. The brothers were both 'small-for-date' babies. The older brother was mildly retarded. Both boys had low immunoglobulin levels in early childhood that gradually rose to the normal range by 4 years of age. Lowry et al. (1989) presented follow-up information on these brothers. They were reexamined at the ages of 17.75 and 15.75 years. Both had restricted elbow extension and the younger brother had bilateral dislocated radial heads. The older brother had developed typical changes of retinitis pigmentosa. The younger brother also had retinitis pigmentosa, although he was not studied as fully as was the older brother (Lowry, 1993).
Nevin et al. (1986) described affected brother and sister with short stature, microcephaly, mental retardation, and multiple epiphyseal dysplasia. They did not have nystagmus. Nevin et al. (1986) concluded that autosomal recessive inheritance was likely. Hankenson et al. (1989) described a brother and sister with epiphyseal dysplasia and microcephaly. They did not have mental retardation or nystagmus.
Brunetti-Pierri et al. (2003) described a patient with microcephaly and multiple epiphyseal dysplasia, but no additional features, suggesting a mild form of Lowry-Wood syndrome. No mutations were found on molecular analysis of the cartilage oligomeric matrix protein gene (600310).
Magnani et al. (2009) described a 17-year-old boy who displayed clinical features consistent with Lowry-Wood syndrome, including microcephaly, short stature, multiple epiphyseal dysplasia, tapetoretinal degeneration, and mental retardation. Bilateral restricted elbow extension, knock knees, and hip dislocation were also present. Radiographs showed evidence of radial dislocation due to absence of radial heads, lateral dislocation of both patellae, multiple epiphyseal dysplasia that was more severe at the proximal femoral epiphyses, and dislocation of both hips with severe dysplasia. Conventional karyotyping was normal; molecular karyotyping by array-based competitive genomic hybridization showed copy number variants that were probably benign. Magnani et al. (2009) suggested that severe hypoplasia or agenesis of the radial heads and multiple joint dislocations (elbows, hips, and knees, including the patellae) might be additional signs of Lowry-Wood syndrome. Shelihan et al. (2018) restudied the patient originally reported by Magnani et al. (2009) and observed deterioration of vision at dusk, further decreased fine dexterity and ability to ambulate, and progression of thoracic scoliosis.
Farach et al. (2018) studied 3 patients with LWS and biallelic mutations in the RNU4ATAC gene, a 10.75-year-old girl (patient 1), an unrelated 14-year-old boy (patient 2), and his 15-year-old sister (patient 3). Patient 1 was an adopted twin who exhibited microcephaly and short stature at birth, as well as an atrial septal defect that closed spontaneously. She had delayed speech and delayed motor milestones. At age 10.75 years, she had short stature and severe microcephaly as well as radiographic findings of multiple epiphyseal dysplasia (MED), brachydactyly with hypoplastic middle phalanges, and fifth-finger brachyclinodactyly. Other features included mild intellectual disability, arachnoid cyst, myopia, and retinitis pigmentosa, as evidenced by absent night vision, loss of peripheral vision, and retinal pigmentary clumping. Immunologic evaluation showed low IgG and IgM levels, without a clear clinical immunodeficiency. Patients 2 and 3 were diagnosed with LWS based on microcephaly, intellectual disability, and MED. Both had short stature, fifth-finger brachyclinodactyly, bilateral elbow contractures, and bilateral femoral head dislocations. In addition, the brother had scoliosis and coxa vara, whereas the sister had mild right knee contracture and coxa valga. They appeared to have normal immune systems and normal vision, but had not undergone formal testing. All 3 patients had similar facial dysmorphisms, including sloping forehead, prominent nose, and full lips.
The transmission pattern of LWS in the families reported by Lowry and Wood (1975) and Nevin et al. (1986) was consistent with autosomal recessive inheritance.
In a 10.75-year-old girl (patient 1) with Lowry-Wood syndrome, in whom previous exome sequencing had not been revealing, Farach et al. (2018) sequenced the RNU4ATAC gene and identified compound heterozygosity for 2 mutations (601428.0001 and 601428.0016). In a similarly affected brother and sister (patients 2 and 3), the authors identified compound heterozygosity for another 2 mutations in RNU4ATAC (601428.0004 and 601428.0017). Farach et al. (2018) noted that microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) and Roifman syndrome (RFMN; 616651), which had been considered clinically distinct from LWS although the 3 disorders share overlapping features, are also caused by biallelic mutation in the RNU4ATAC gene. Because some patients may exhibit phenotypic overlap and not fit clearly into a particular diagnosis, the authors suggested that targeted RNU4ATAC sequencing should be considered in undiagnosed patients with any combination of epiphyseal dysplasia with intellectual disability, microcephaly, immunodeficiency, and/or retinal anomalies.
In a 19-year-old patient with LWS (patient 1), who was originally described by Brunetti-Pierri et al. (2003), Shelihan et al. (2018) performed whole-exome sequencing (WES) that failed to reveal plausible candidate variants. Following the report by Farach et al. (2018), reanalysis of the WES data identified compound heterozygosity for pathogenic variants in the RNU4ATAC gene (601428.0018 and 601428.0019). In a 28-year-old man with LWS (patient 2), who was originally reported by Magnani et al. (2009) and in whom WES was initially unfruitful, reanalysis also revealed variants in RNU4ATAC (601428.0020 and 601428.0021).
Brunetti-Pierri, N., De Brasi, D., Ikegawa, S., Camera, G., Andria, G., Sebastio, G. A new patient with Lowry-Wood syndrome with mild phenotype. Am. J. Med. Genet. 118A: 68-70, 2003. [PubMed: 12605445] [Full Text: https://doi.org/10.1002/ajmg.a.20008]
Farach, L. S., Little, M. E., Duker, A. L., Logan, C. V., Jackson, A., Hecht, J. T., Bober, M. The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome. Am. J. Med. Genet. 176A: 465-469, 2018. [PubMed: 29265708] [Full Text: https://doi.org/10.1002/ajmg.a.38581]
Hankenson, L. G., Ozonoff, M. B., Cassidy, S. B. Epiphyseal dysplasia with coxa vara, microcephaly, and normal intelligence in sibs: expanded spectrum of Lowry-Wood syndrome? Am. J. Med. Genet. 33: 336-340, 1989. [PubMed: 2801767] [Full Text: https://doi.org/10.1002/ajmg.1320330310]
Lowry, R. B., Wood, B. J., Cox, T. A., Hayden, M. R. Epiphyseal dysplasia, microcephaly, nystagmus, and retinitis pigmentosa. Am. J. Med. Genet. 33: 341-345, 1989. [PubMed: 2801768] [Full Text: https://doi.org/10.1002/ajmg.1320330311]
Lowry, R. B., Wood, B. J. Syndrome of epiphyseal dysplasia, short stature, microcephaly and nystagmus. Clin. Genet. 8: 269-274, 1975. [PubMed: 1183069] [Full Text: https://doi.org/10.1111/j.1399-0004.1975.tb01502.x]
Lowry, R. B. Personal Communication. Calgary, Alberta, Canada 2/24/1993.
Magnani, C., Tedesco, S. A., Dallaglio, S., Sommi, M., Bacchini, E., Vetro, A., Zuffardi, O., Bevilacqua, G. Multiple joint dislocations: an additional skeletal finding in Lowry-Wood syndrome? Am. J. Med. Genet. 149A: 737-741, 2009. [PubMed: 19288552] [Full Text: https://doi.org/10.1002/ajmg.a.32773]
Nevin, N. C., Thomas, P. S., Hutchinson, J. Syndrome of short stature, microcephaly, mental retardation, and multiple epiphyseal dysplasia--Lowry-Wood syndrome. Am. J. Med. Genet. 24: 33-39, 1986. [PubMed: 3706411] [Full Text: https://doi.org/10.1002/ajmg.1320240106]
Shelihan, I., Ehresmann, S., Magnani, C., Forzano, F., Baldo, C., Brunetti-Pierri, N., Campeau, P. M. Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype. Hum. Genet. 137: 905-909, 2018. [PubMed: 30368667] [Full Text: https://doi.org/10.1007/s00439-018-1950-8]