Desbuquois Dysplasia 2

A number sign (#) is used with this entry because of evidence that Desbuquois dysplasia-2 (DBQD2) is caused by homozygous or compound heterozygous mutation in the XYLT1 gene (608124) on chromosome 16p12.

Description

Desbuquois dysplasia, which belongs to the multiple dislocation group of disorders, is characterized by dislocations of large joints, severe pre- and postnatal growth retardation, joint laxity, and flat face with prominent eyes. Radiologic features include short long bones with an exaggerated trochanter that gives a 'monkey wrench' appearance to the proximal femur, and advanced carpal and tarsal ossification (summary by Bui et al., 2014).

For a discussion of genetic heterogeneity of Desbuquois dysplasia, see DBQD1 (251450).

Nomenclature

Desbuquois dysplasia had been classified as 'type 1' or 'type 2' based on the presence (type 1) or absence (type 2) of additional hand anomalies, consisting of an extra ossification center distal to the second metacarpal, a delta phalanx, a bifid distal thumb phalanx, and dislocation of the interphalangeal joints. However, patients with and without these additional hand anomalies have been reported to have mutations in the same gene (see, e.g., CANT1, 613165); thus, these features are not distinctive criteria to predict the molecular basis of DBQD (Furuichi et al., 2011).

Clinical Features

Schreml et al. (2014) described a Turkish sister and brother who had short stature at birth and progressive growth retardation, with height, weight, and head circumference below the 3rd centile in adulthood. Facial dysmorphism included synophrys, deep nasal ridges, full lips, puffy or doughy appearance of skin, relative macrocephaly, and long philtrum; they also exhibited broad thumbs, clinodactyly, coxa valga, and flat feet with doughy plantar skin. Both patients had acne, and hirsutism was noted in the female. Extensive endocrine evaluation was normal, as were glycosylation, lysosomal, leukocyte, and fibroblast studies. X-rays showed mild skeletal changes, with plump and stocky long bones, short femoral necks, and broad ribs, and the clavicles appeared shortened. Both sibs had moderate intellectual disability. Bui et al. (2014) noted that although the affected sibs in this family did not exhibit a 'monkey wrench' appearance of the femoral neck or advanced carpal bone age, these features disappear with time in the course of DBQD. The sibs had other features that were reminiscent of the DBQD spectrum, including coxa valga, broad thumbs, abnormal feet, and truncal obesity.

Bui et al. (2014) studied 20 individuals who fulfilled the diagnostic criteria for DBQD type 2, including severe pre- and postnatal short stature, short extremities, dislocations with 'monkey wrench' appearance of the femora, short long bones with metaphyseal widening, epiphyseal dysplasia, and advanced carpal and tarsal ossification. Two of the patients were a sister and brother born to healthy consanguineous Tunisian parents; at birth, both sibs had severe short stature, hypotonia, flat face with prominent eyes, hyperlaxity, hip dislocation, and narrow thorax leading to respiratory distress that resolved during the first year of life. Skeletal x-rays showed 'monkey wrench' appearance of the femoral neck, epiphyseal dysplasia, knee dislocation, and advanced carpal bone age. Both sibs had intellectual disability.

Baratela et al. (2012) described 7 male patients from 6 families of different ethnic backgrounds with a syndrome of skeletal dysplasia, characteristic facial features, and developmental delay. Skeletal findings included patellar dislocation, mild metaphyseal changes, brachydactyly and brachymetacarpalia with stub thumbs, short femoral necks, flat acetabular roofs, 'monkey-wrench' appearance of proximal femur, and platyspondyly. All patients exhibited a flattened midface with broad and depressed nasal bridge; other facial features included cleft palate or bifid uvula, epicanthal folds, and synophrys in some patients. Cognitive developmental delay with shortened attention span was present, although somewhat masked by a warm and engaging personality. Baratela et al. (2012) noted phenotypic overlap with Desbuquois dysplasia, particularly with patients having a CANT1 (613165)-negative form of DBQD.

Inheritance

Because all 7 of their patients were male, Baratela et al. (2012) suggested that inheritance of the disorder was most likely X-linked recessive. However, both Schreml et al. (2014) and Bui et al. (2014) reported affected sister/brother sib pairs, consistent with autosomal recessive inheritance.

Mapping

In a consanguineous Turkish family in which a sister and brother had short stature, skeletal anomalies, and intellectual disability, Schreml et al. (2014) performed genomewide linkage analysis and found the largest homozygous regions on chromosome 16.

Molecular Genetics

Schreml et al. (2014) performed whole-exome sequencing in a Turkish man from a consanguineous family with short stature, skeletal anomalies, and intellectual disability mapping to chromosome 16, and identified homozygosity for a missense mutation in the XYLT1 gene (R481W; 608124.0002). Sanger sequencing confirmed that the mutation was present in homozygosity in his affected sister and in heterozygosity in their unaffected parents. Functional analysis showed that R481W represents a hypomorphic allele. Bui et al. (2014) suggested that the relatively mild phenotype observed in these sibs might be due to a partial loss of function.

In 2 sibs with DBQD2 from a consanguineous Tunisian family, Bui et al. (2014) performed whole-exome sequencing and identified homozygosity for a missense mutation in the functionally relevant XYLT1 gene (R598C; 608124.0003). The mutation was confirmed by direct sequencing, and their unaffected parents were found to be heterozygous for the mutation. Analysis of the XYLT1 gene in 11 more DBQD families revealed homozygosity for 4 additional XYLT1 mutations in 5 unrelated patients, including 1 frameshift, 1 nonsense, and 2 splice site mutations (608124.0004-608124.0007). All mutations, which segregated with disease in each family, were undetected in 200 control chromosomes. In addition to the skeletal findings, 5 of the 7 mutation-positive patients had intellectual disability, and 2 exhibited truncal obesity.

In 12 patients from 10 unrelated families exhibiting a skeletal syndrome with features overlapping those of DBQD2, including 6 patients from 5 families originally reported by Baratela et al. (2012), LaCroix et al. (2019) identified homozygous and compound heterozygous mutations in the XYLT1 gene (see, e.g., 608124.0008-608124.0012). Eleven of the 12 patients were male; the authors noted that previous reports of patients with DBQD2 did not show the same skewing, and suggested that larger cohorts were needed to determine whether a true sex bias exists.

Exclusion Studies

Because of phenotypic overlap between the features of their patients and those observed in Desbuquois dysplasia, Baratela et al. (2012) sequenced the CANT1 gene (613165) in all 7 of their patients. The coding regions of exons 3, 4, and 5 were normal, and no deletions were identified in the 5-prime UTR/exon 1 region of the gene.