First Report of Two Egyptian Patients with Desbuquois Dysplasia due to Homozygous CANT1 Mutations

Abstract

Desbuquois dysplasia type 1 (DBQD1) is a very rare skeletal dysplasia characterized by growth retardation, short stature, distinct hand features, and a characteristic radiological monkey wrench appearance at the proximal femur. We report on 2unrelated Egyptian patients having the characteristic features of DBQD1 with different expressivity. Patient 1 presented at the age of 45 days with respiratory distress, short limbs, faltering growth, and distinctive facies while patient 2 presented at 5 years of age with short stature and hypospadias. The 2 patients shared radiological features suggestive of DBQD1. Whole-exome sequencing revealed a homozygous frameshift mutation in the CANT1 gene (NM_001159772.1:c.277_278delCT; p.Leu93ValfsTer89) in patient 1 and a homozygous missense mutation (NM_138793.4:c.898C>T; p.Arg300Cys) in patient 2. Phenotypic variability and variable expressivity of DBQD was evident in our patients. Hypoplastic scrotum and hypospadias were additional unreported associated findings, thus expanding the phenotypic spectrum of the disorder. We reviewed the main features of skeletal dysplasias exhibiting similar radiological manifestations for differential diagnosis. We suggest that the variable severity in both patients could be due to the nature of the CANT1 gene mutations which necessitates the molecular study of more cases for phenotype-genotype correlations.

Keywords: CANT1; Desbuquois dysplasia; Genotype-phenotype correlation; Hyperphalangism; Prominent lesser trochanter.

Fig. 1

a Pedigree of patient 1. b–d Phenotypic characteristics of patient 1. b Full-body image with flat face, prominent eyes with blue sclera, depressed nasal bridge, long philtrum, microretrognathia, short neck and very short limbs with Michelin tire creases in upper limbs, short thorax and pectus carinatum. c Right hand showing brachydactyly with clinodactyly of all fingers with lateral deviation of the 2nd and 3rd fingers and dysplastic nails. d Short flat feet with low insertion of the big toes, dysplastic nails, medial deviation of left 2nd to 5th toes and overlapping left 2nd and 4th toes over the 3rd toe. e–g Radiographic features of patient 1. e X-ray PA view of the hands of patient 1 at 40 days showing short metacarpals and delta phalanx (extra ossification center distal to the 2nd metacarpal; arrows), extra carpal ossification centers, dislocation of 1st and 2nd metacarpophalangeal joints. f X-ray of the legs and feet showing short tubular bones, short medially deviated feet with short metatarsals and lateral deviation of 1st metarsals and 1st toes. g X-ray of the whole infant's body showing short thorax with narrow space between ribs, flat acetabular roof and prominent lesser trochanter giving the appearance of Swedish key of the proximal femur (notched arrow).

Fig. 2

a Pedigree of patient 2. b–e Phenotypic characteristics of patient 2. b Whole-body image with short-limbed short stature, short neck, flat feet, bow legs, and left knee showing genu recurvatum. c Face showing prominent eyes with blue sclera, small low-set cupped ears with overfolded ear helix, flat nasal bridge, microstomia, micrognathia. d Hands with bilateral clinodactyly of 2nd finger and low-set thumb. e Flat feet with bilateral wide sandal gap and medial deviation of all toes. f–i Radiographic features of patient 2. f X-ray of the hands and forearms of patient 2 at the age of 5 years showing brachydactyly, clinodactyly of index fingers with extra delta phalanx between the distal end of 1st metacarpal and base of proximal phalanx (arrow), multiple dislocations at phalanges and metacarpophalangeal joints, hypoplastic flattened epiphyses of the distal end of radius and irregular metaphysis of both radius and ulna. g X-ray of the feet showing extra tarsal ossification centers (arrows), bilateral broad medially deviated 1st metatarsal, and bilateral irregular distal phalanx of big toe. h X-ray of the spine and pelvis AP and lateral view showing absent epiphysis at head of femur mild platyspondyly and kyphosis of vertebrae. i X-ray of the lower limbs showing short tubular bones, epiphyseal dysplasia, short neck of femur and prominent lesser trochanter with Swedish key appearance, bilateral wide irregular metaphysis and hypoplastic epiphysis around the knees and ankles.