Additional three patients with Smith-McCort dysplasia due to novel RAB33B mutations

Clinical Reports

Patient 1, 7-year-old male child, presented with short stature, chest deformity, recurrent episodes of lower respiratory tract infections and frequent episodes of vomiting. He had an abnormal gait and was not able to squat. Progressive difficulty in walking was also noticed since the age of 3 years. He was the third child to a non-consanguineous couple with no other significant family history. He was born at full term by normal vaginal delivery and had a birth weight of 2.5 kg (2 SD below the mean). His developmental milestones were normal. On examination at age 7 years, his height was 110.5 cm (2 SD below the mean), head circumference was 52 cm (normal), weight was 32 kg (2 SD above the mean) and upper segment to lower segment ratio was 0.97. His phenotype included a short neck, pectus carinatum, limited extension of elbows and genu valga (Figs. 1A,D and 2D). Brachydactyly and pes planus were also noticed (Fig. 2A and G). There was no organomegaly. Hematology and biochemical investigations were unremarkable.

Patient 2, was the first born to a fourth degree consanguineous couple. Antenatal period was unremarkable. Sonographic antenatal screening at 34–35 weeks revealed no skeletal abnormality. He was born at term by forceps delivery with a birth weight of 2.75 kg. There were no neonatal complications. All motor and sensory milestones were appropriate for his age when assessed at age 4 years. He was investigated for poor weight gain, abnormal walking, and short stature. Initially, he was suspected to have mucopolysaccharidosis IV, which was investigated and was not confirmed. At age 12 years and 9 months, his height was 126 cm (4 SD below the mean), weight was 31.6 kg (2 SD below the mean), and head circumference was 52 cm (normal). He presented small forehead, posteriorly rotated ears, mild prognathism, and facial appearance was similar to Morquio syndrome. He showed severe pectus carinatum, lumbar lordosis, genu valgum, brachydactyly in hands, and overlapping of toes T2 and T3 bilaterally (Figs. 1B,E and 2B, E, and H). Rest of the systemic examination including neuromuscular system, blood counts, serum chemistry were unremarkable.

Patient 3 presented with short stature and marked genu valgum deformity at age 31 years. His birth weight and height were recalled to be within normal limit, but delayed height gain was noticed since 2 years of age. Developmental milestones were within normal limits. He was short but physically active with mild genu valgum until 6 years of age. Then, genu valgum gradually aggravated and he underwent surgical correction by distal femoral osteotomy at age 9 years. He did not have any medical check-up thereafter. Genu valgum recurred and aggravated, and hip joint pain and weakness developed around age 14 years, making walking upstairs difficult and Taylor position impossible (Fig. 2F). At 16 years of age, the patient presented with painful limitation of hip abduction, and was wheelchair-bound. He was 107.5 cm (7–8 SD below mean) and 17.5 kg (5 SD below mean) at age 14 years, and the final height at age 31 years was 115 cm (8–9 SD below mean).

He had myopia, but did not show signs of hearing loss. Physical examination showed increased knee jerk and borderline Babinski signs. Plain radiograph and MRI showed atlantoaxial instability and compressive myelopathy. He could barely stand up with due to externally rotated and flexed hips and the patellae facing laterally. The femorotibial angle was over 50 degrees, but was difficult to determine because of ligamentous laxity. He had thoracolumbar kyphosis and increased anteroposterior distance of the thoracic cage (Fig. 1C,F). Feet and hands were small for the body size (Fig. 2C,I). There was a remarkable resemblance of the clinical and radiographic features to Morquio syndrome. Survey for urinary, enzymatic, and molecular study of MPS IV revealed no abnormalities.

Skeletal survey of all three patients showed predominant abnormalities of the spine and pelvic bones, mildly affected epi-metaphyses of the long bones, and brachydactyly. Presence of platyspondyly exhibiting a central constriction of the upper and lower end-plates of the vertebral bodies, also called “double humped appearance” was seen at an early age but became less distinct with age (Fig. 3A–C).

The iliac bones were small, with tapering lower ends, and thick ischial and pubic bones. A distinctive and diagnostic lacy appearance of the iliac crest was evident but disappeared in adult patient (Fig. 3D–F). Brachydactyly with consistently short metacarpals and dysplastic carpal bones was observed (Fig. 4).

Clinical and radiological features of the current and reported patients with mutations in RAB33B are listed in Table I.

Mutation Analysis

Genomic DNA from all three patients was sequenced for the entire coding region as well as the splice sites of DYM gene. There was no significant sequence variation from the reference genome. Sequencing of RAB33B gene revealed homozygous novel sequence variants, c.211C>T (p.R71*) in exon one of patient one, c.365T>C (p.F122S) in exon two of patient two and compound heterozygous variants c.48delCGGGGCAG (p.G17Vfs*58) and c.490C>T (p.Q164*) in exons 1 and 2, respectively, of patient three (Fig. 5). The biallelic segregation was confirmed by sequencing parents’ samples in all the three families. The four variants reported here were not present in dbSNP, 1000 genome project or Exome Aggregation Consortium (ExAC) database. Conservation analysis of human RAB33B protein with other species showed that the variant c.365T>C resulted in the substitution of phenylalanine by serine at a highly conserved codon 122 (Fig. 6). This variant was also found to be damaging by pathogenicity prediction tools MutationTaster, SIFT, and PolyPhen-2. The other three variations were seen to be protein truncating mutations.