Desbuquois Dysplasia 1

A number sign (#) is used with this entry because of evidence that Desbuquois dysplasia-1 (DBQD1) is caused by homozygous or compound heterozygous mutation in the CANT1 gene (613165) on chromosome 17q25.

Description

Desbuquois dysplasia (DBQD) is an autosomal recessive chondrodysplasia belonging to the multiple dislocation group and characterized by severe prenatal and postnatal growth retardation (stature less than -5 SD), joint laxity, short extremities, and progressive scoliosis. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advanced carpal and tarsal bone age with a delta phalanx (summary by Huber et al., 2009).

Desbuquois dysplasia is clinically and radiographically heterogeneous, and had been classified into 2 types based on the presence (type 1) or absence (type 2) of characteristic hand anomalies, including an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and dislocation of the interphalangeal joints (Faivre et al., 2004). However, patients with and without these additional hand anomalies have been reported to have mutations in the same gene (see, e.g., CANT1); thus, these features are not distinctive criteria to predict the molecular basis of DBQD (Furuichi et al., 2011). In addition, Kim et al. (2010) described another milder variant of DBQD with almost normal outwardly appearing hands, but significant radiographic changes, including short metacarpals, elongated phalanges, and remarkably advanced carpal bone age. However, there is no accessory ossification center distal to the second metacarpal, and patients do not have thumb anomalies. Similar changes occur in the feet. These patients also tend to develop precocious osteoarthritis of the hand and spine with age. This phenotype is sometimes referred to as the 'Kim variant' of DBQD (Furuichi et al., 2011).

Genetic Heterogeneity of Desbuquois Dysplasia

DBQD2 (615777) is caused by mutation in the XYLT1 gene (608124) on chromosome 16p12.

Two unrelated patients with immunodeficiency-23 (IMD23; 615816), due to mutation in the PGM3 gene (172100), were reported to have skeletal features reminiscent of DBQD.

Clinical Features

Beemer et al. (1985) and Meinecke et al. (1989) described an apparently distinct skeletal dysplasia manifested by micromelic dwarfism, narrow chest, vertebral and metaphyseal abnormalities and advanced carpotarsal ossification. They considered the disorder described by Desbuquois et al. (1966) in 2 sisters to be the same disorder and on the basis of this suggested autosomal recessive inheritance. The patients of Desbuquois et al. (1966), aged 8 years and 20 months, showed chondrodystrophy with severe dwarfism, dislocation of the patellas and hips, glaucoma, and mental retardation. Piussan et al. (1975) reported 6 children with comparable clinical and radiologic findings. The patients of Anderson et al. (1982) and Pazzaglia et al. (1988) also appear to have had this disorder. The differential diagnosis of Desbuquois syndrome includes some conditions that have been lumped under the heading of Larsen syndrome (245600). Le Merrer et al. (1991) suggested that cases II and III and possibly case IV of Silverman (1972) had Desbuquois syndrome rather than Larsen syndrome. The findings in the hand in Desbuquois syndrome are particularly distinctive. There are extraossification centers, e.g., extra phalanges, causing deviation of the fingers. These findings may not be discernible after the age of about 1 year. Infants under 1 year of age also show coronal clefts of the vertebrae. Le Merrer et al. (1991) reported 3 patients with Desbuquois syndrome who showed deviation of digits and supernumerary metacarpal bones. Two of them were born of consanguineous parents. Affected sisters were reported by Desbuquois et al. (1966) and by Pazzaglia et al. (1988).

Shohat et al. (1994) defined the clinical, radiographic, and morphologic features of 7 cases from 3 sibships. All had severe rhizomelic short stature manifested in utero, which allowed a second trimester ultrasound diagnosis. The children had a round flat face, micrognathia, and long upper lip with flat philtrum. At least one had lethal severe respiratory distress associated with small thorax and others had recurrent moderate to severe respiratory distress syndrome (RDS) during infancy. All patients had generalized joint laxity with dislocatable knees and/or femora. Particularly characteristic changes were noted in the fingers, which were radially deviated at the metacarpophalangeal and proximal interphalangeal joints, with broad, proximally placed hitchhiker thumbs and mild clinodactyly of the fifth fingers. Radiographic changes included a supernumerary ossification center between the proximal phalanx of the index finger and the second metacarpal. The femoral necks showed enlargement of the lesser trochanter with metaphyseal beaking, producing a characteristic 'monkey wrench,' or 'Swedish key,' appearance. Growth plate cartilage showed dilated cisterns of rough endoplasmic reticulum in reserve zone chondrocytes. Shohat et al. (1994) pointed out that the radiographic changes in the hands are similar to those in Catel-Manzke syndrome (616145).

Hand anomalies consisting of phalangeal dislocations and an extra ossification center distal to the second metacarpal are not observed in all Desbuquois patients, having been reported in a third of cases (Gillessen-Kaesbach et al., 1995).

Faivre et al. (2004) provided follow-up on 4 patients (3 males and 1 female) with Desbuquois syndrome, aged 16 to 22 years. The patients had previously been described by Piussan et al. (1975) and Le Merrer et al. (1991). Only 1 patient (case 1 of Le Merrer et al., 1991) had typical hand abnormalities. Mean height in adulthood was 114 cm (-8.5 SD) with progressive deceleration of growth from birth (-4 SD) to adulthood. Facial features (round flat face, prominent eyes, and midface hypoplasia) were still present but less obvious than in childhood. Joint laxity was persistent. Orthopedic complications included coxa vara or valga (3/4), scoliosis (3/4), marked lordosis (3/4), and ambulatory difficulties (3/4). Radiographs demonstrated generalized osteoporosis, especially of the spine, and generalized brachydactyly, with short distal phalanges due to a precocious fusion of the distal phalangeal epiphyses. The 'Swedish key' appearance of the proximal femora is less obvious with age, but with elevated greater trochanters. Scoliosis and/ or lordosis is seen but vertebral clefts disappear in adults. Acute open angle glaucoma was seen in 1 patient. Glaucoma was also noted in 1 patient described by Desbuquois et al. (1966). Faivre et al. (2004) suggested that ophthalmologic examination with assessment of ocular pressure be part of routine follow-up in patients with Desbuquois syndrome.

Faden et al. (2010) reported a male infant, born of consanguineous Saudi Arabian parents, with Desbuquois dysplasia. He had micromelia, severe growth retardation, clubfeet, dysmorphic facial features, hypotonia, short neck, widely spaced nipples, and protuberant abdomen. Radiographs showed typical hand findings with 2 supernumerary ossification centers and phalangeal dislocations, vertebral bodies with coronal clefting, and spur-like projections in the lesser trochanters. He also had bilateral congenital glaucoma. Three older sibs had died in the neonatal period of a similar disorder.

Baynam et al. (2010) reported recurrence of hydrop lethal DBQD in 2 offspring of a nonconsanguineous Caucasian couple of Australian origin. Prenatal ultrasound of an affected fetus at 19 weeks' gestation showed short long bones, small thorax, little limb movement, and fixed abduction of the hips. The hands were held in an unusual position with a gap between the central digits. The pregnancy was terminated, and postmortem examination showed hydrops, a round face, short long bones, vertebral body hypoplasia, a gap between the index and middle finger, hypoplasia of the thumbs and great toes, abnormal positioning of the second and third phalanges with an extra ossification center distal to the second metacarpal, and hypoplastic vertebral bodies with coronal clefts. Light microscopy showed attenuation of the femoral epiphysis and chondrocyte hyperplasia. The subsequent pregnancy was terminated at 12 weeks' gestation following identification of similar features. Swedish key femoral heads were not observed, possibly due to early fetal ascertainment. Baynam et al. (2010) suggested that the widely splayed fingers resembled the Greek capital letter 'Upsilon,' and may be a useful diagnostic handle. Furuichi et al. (2011) identified compound heterozygous mutations in the CANT1 gene (613165.0009 and 613165.0011) in 1 of the fetuses reported by Baynam et al. (2010).

Laccone et al. (2011) reported 3 unrelated German fetuses with a severe form of Desbuquois dysplasia diagnosed by prenatal ultrasound and followed by termination at ages 25, 21, and 17 weeks' gestation. All 3 male fetuses were hydropic and showed similar features, including brachymelic dwarfism, short neck and trunk, distended abdomen, and a large cranium with high forehead. The faces were round and flat with short midfaces, short, flat, broad noses with anteverted nares, microstomia, and microretrognathia. The eyes were upslanted with proptosis and epicanthal folds, and the ears were dorsally rotated and overfolded. One fetus had cystic hygroma of the neck. The hands showed radial deviation and clinodactyly of the index fingers and low inserting broad thumbs with dysplastic nails. The feet were clubbed, with low inserting and short big toes. Radiographic studies showed mild shortening and bowing of long bones with slightly flared metaphyses, and a protuberant lesser trochanter. Only case 1, at 25 weeks' gestational age, showed a monkey wrench appearance of the proximal femora. There was shortening of the first metatarsals and of the first and second metacarpals, duplication or splitting of the distal phalanx of the thumbs, and a small laterally displaced extra phalangeal bone at the base of both index fingers. The femoral heads appeared dislocated, with narrow horizontal acetabular roofs. The thorax was narrow and bell shaped, and the ribs were thin. Histologic examination of the long bones revealed crowding of enlarged resting chondrocytes, and short, irregular columns with ovoid groupings of chondrocytes. All had renal anomalies, such as ureteropelvic dilatation, horseshoe kidney, and renal cysts. In 2 families, previously affected sibs had died in infancy of respiratory failure due to skeletal disorders. In all 3 fetuses, Laccone et al. (2011) identified homozygous or compound heterozygous mutations in the CANT1 gene, with 1 suggestive of a founder effect (228_229insC; 613165.0009).

Nizon et al. (2012) identified a CANT1 mutation (613165.0015) in a patient with atypical DBQD, without any accessory center but with major finger dislocations, epiphyseal interphalangeal anomalies, and thumb digitalization, thus expanding the phenotypic spectrum of hand anomalies observed with CANT1 mutations.

Kim Variant of Desbuquois Dysplasia

Nishimura et al. (1999) described the clinical and radiologic features of a skeletal dysplasia resembling Desbuquois dysplasia, but with a milder phenotype, on the basis of a pair of sibs, a sporadic case, and 1 previously reported patient (Nishimura et al., 1996). The patients were of Japanese or Korean origin. The skeletal alterations, including generalized osteopenia, mild modification of the vertebral endplates, epiphyseal flattening of the long bones, broad proximal femora with a spur-like projection of the lesser trochanters (a monkey wrench appearance of the proximal femurs), and advanced carpal skeletal age, were almost identical to those of Desbuquois dysplasia. However, postnatal growth failure and minor spondyloarticular problems in the disorder in these patients contrasted with the conspicuous prenatal growth failure and severe spondyloarticular deformities of Desbuquois dysplasia. An additional ossification center at the second phalangeal base was not observed, and most had normal psychomotor development. Short stature did not reach the degree seen in Desbuquois dysplasia. The molecular investigation of 1 patient excluded abnormalities of the diastrophic dysplasia sulfate transporter gene (DTDST; 606718). Nishimura et al. (1999) suggested that these patients represent a mild variant of Desbuquois dysplasia.

Al Kaissi et al. (2005) described 3 Tunisian sibs with a rare assortment of clinical and radiologic abnormalities closely resembling Desbuquois dysplasia. However, the sibs had normal facies, normal hands, and normal intelligence. Severe musculoskeletal distinguishing features included joint stiffness, severe kyphoscoliosis, and multiple large joint dislocations. An additional radiographic feature not reported in Desbuquois dysplasia was multiple carpal ossification centers. Al Kaissi et al. (2005) remarked that the diagnosis of Desbuquois dysplasia is more difficult in older children and adults as the characteristic facial features of early childhood may recede and the metaphyseal growth plates obliterate.

Kim et al. (2010) reported a less severe variant of DBQD in 7 patients, including 2 pairs of sibs. One pair of sibs had previously been reported by Nishimura et al. (1999). Three patients were in their twenties, 1 was 12 years old, 2 were 6 years old, and 1 was almost 3 years old. All had normal intelligence. The patients had characteristic findings of the disorder, including short stature, round face with flat nose and protruding eyes, and multiple joint dislocations and laxity, particularly affecting the knee. Radiographic criteria included a 'monkey wrench' appearance of the proximal femora, epimetaphyseal dysplasia at the knees, and advanced carpal/tarsal bone age. Radiographic studies showed markedly advanced carpal age with metacarpal shortness that became more conspicuous with age. The proximal and middle phalanges were nearly normal or slightly elongated, but the distal phalanges were very short, resulting in a nearly equal length of the second to fourth or fifth finger. Three patients also had advanced tarsal bone age. Metatarsal adductus and varus were evident in all patients to varying degrees. The metatarsals were short, but the phalanges were elongated, particularly at the second and third toes. None had an accessory ossification center or thumb anomalies. After about age 15 years, radiographs showed precocious degenerative arthritis in the carpal bones and interphalangeal joints. The 'monkey wrench' appearance seemed to change with time: the femoral neck became bulky due to an enlarged and elevated greater trochanter, and the short and wide intertrochanteric portion became more accentuated. Prominent lesser trochanters were noted in 4 patients after the age of 12 years. The hip joints showed premature degenerative osteoarthritis with age. All patients also had kyphoscoliosis with vertebral endplate irregularities and narrowing of the disc space; the older ones developed progressive degenerative spondylosis.

Diagnosis

Faivre et al. (2004) described the radiologic features of 35 patients with Desbuquois dysplasia. The diagnosis was based on the presence of marked short stature of prenatal onset, joint laxity, 'Swedish-key' appearance of the proximal femur, and advanced carpal and tarsal ossification. Three additional radiographic features were defined for the diagnosis: flat acetabular roof, elevated greater trochanter, and proximal fibular overgrowth. Faivre et al. (2004) divided the 35 patients into 2 groups: Group 1 (46%) with typical hand changes (e.g., accessory ossification center at the base of the proximal phalanx of the second digit and/or a delta phalanx of the thumb), and Group 2 (54%) without hand abnormalities. Group 1 had a higher frequency of long bone dislocations (62% vs 28%) and kyphoscoliosis (50% vs 12%).

Mapping

Two distinct groups of Desbuquois patients can be defined on the basis of the presence or absence of hand anomalies. Faivre et al. (2003) performed a genomewide search in 4 inbred Desbuquois families with typical hand anomalies originating from France, Sri Lanka, the United Arab Emirates, and Morocco. By homozygosity mapping, they identified a 9.5-cM interval on chromosome 17q25.3. They obtained a maximum lod score of 4.61 at theta = 0.0 for locus D17S1806. This study supported the genetic homogeneity of the clinical subtype with hand anomalies.

Heterogeneity

In 3 affected individuals from unrelated consanguineous families with Desbuquois dysplasia without hand abnormalities, Faivre et al. (2004) found heterozygosity for 9 microsatellite DNA markers from the 17q25.3 region, thus excluding that region as the locus in Desbuquois families with no hand anomalies and demonstrating genetic heterogeneity.

Molecular Genetics

In 10 affected children from 9 families with Desbuquois dysplasia, Huber et al. (2009) identified 7 distinct mutations, including 3 missense and 4 truncating mutations, in the CANT1 gene (613165.0001-613165.0007) in homozygous or compound heterozygous state. Eight of the families were consanguineous. The mutations were not found in 210 control chromosomes. All of the affected children presented with similar skeletal manifestation, but an early death due to cardiorespiratory failure was observed in children with truncating mutations.

Faden et al. (2010) identified a homozygous truncating mutation in the CANT1 gene (613165.0008) in a Saudi Arabian male infant, born of consanguineous parents, with Desbuquois dysplasia,

Furuichi et al. (2011) identified homozygous or compound heterozygous mutations in the CANT1 gene (see, e.g., 613165.0011-613165.0014) in affected members of 7 families with DBQD, including 1 fetus with 'type 1' DBQD (Baynam et al., 2010), 1 child with 'type 2' DBQD, and 5 patients with the so-called 'Kim variant,' 4 of whom had been described by Kim et al. (2010). All patients with the Kim variant had a V226M mutation (613165.0013) on at least one allele. The findings indicated that all 3 variants of the disorder represent a phenotypic spectrum caused by mutation in the CANT1 gene. The mutations included 3 nonsense and 5 missense mutations, resulting in a loss of enzyme function. There were no apparent genotype/phenotype correlations. Furuichi et al. (2011) concluded that the presence or absence of an additional metacarpal ossification center cannot be a distinctive criterion to predict the molecular basis of DBQD.

Nizon et al. (2012) performed direct sequencing of the exons and the exon-intron boundaries of the CANT1 and CHST3 (603799) genes in 38 DBQD patients (6 type 1, 1 Kim variant, and 31 type 2 patients) and identified 8 distinct CANT1 mutations, 5 of which were novel. Missense and nonsense mutations were found in all 6 type 1 patients and in the 1 Kim variant patient; a splice site mutation (-342+1G-A; 613165.0015) was found in 1 atypical type 2 patient (patient 8) with no accessory center but with major finger dislocations, epiphyseal interphalangeal anomalies, and thumb digitalization. To analyze the effect of the intronic splice site mutation, Nizon et al. (2012) performed CANT1 cDNA analysis on RNA extracted from the patient's leukocytes and found no product by RT-PCR, supporting an absence of CANT1 mRNA transcription due to 5-prime UTR splice site alteration. A mutation in the CHST3 gene was identified in a patient initially diagnosed with DBQD type 2. The same mutation in CHST3 (L259P; 603799.0002) had been found in patients with SED with joint dislocations (143095) and Nizon et al. (2012) noted the phenotypic overlap between the 2 disorders.

Population Genetics

By haplotype analysis of 5 families of Japanese and Korean origin with the Kim variant and the CANT1 V226M mutation (613165.0013) reported by Furuichi et al. (2011), Dai et al. (2011) demonstrated a founder effect. The age of the mutation was estimated at about 1,420 years, around the time of the late Kofun era.