Diastrophic dysplasia (DTD), or diastrophic dwarfism, is an uncommon genetic pathology falling under the group of skeletal dysplasias [1]. It is a progressive condition conducting to physical disability [2]. The first signs of DTD are observed at birth and develop following the defects in cartilage buildup process, affecting skeletal formation. Additionally, respiratory complications may lead to increased mortality in children with DTD in the neonatal period [3]. The associated symptomatic findings include their severity and range, showing a wide diversity in separate cases. Concurrently, the clinical features often include limb shortening (short-limbed dwarfism) and short stature; defective development of joints (joint dysplasia) and bone structure (skeletal dysplasia) in many body regions; progressive pathological spine curvature (predominantly scoliosis and/or kyphosis); pathological changes in the pinnae tissue (external ear parts); they may also include craniofacial area malformations [4, 9, 11, 21]. IQ is usually normal.
The diagnosis is based on the presence of pathogenic variants in
More than 300 genes were reported to be involved in skeletal dysplasia with autosomal recessive (AR), autosomal dominant and X-linked manner (Table 1). Clinical signs of all these diseases have similar manifestations and a comparable phenotype, thus only genetic testing results can state the appropriate diagnosis and determine the disorder risk for relatives. The type of inheritance and genes associated with different forms of skeletal dysplasia are presented in the Table 1. The prevalent skeletal dysplasia type is
The type of inheritance and genes associated with different forms of skeletal dysplasia
Group or name of the disorder FGFR3 disorders | Mode of Inheritance | Gene Symbol |
---|---|---|
Thanatophoric dysplasia | AD | |
Achonodroplasia | AD | |
Hypochondroplasia | AD | |
SADDNA | AD | |
Achondrogenesis II | AD | |
Hypochondrogenesis | AD | |
Spondyloepiphyseal dysplasia congenita (SEDC) | AD | |
Kniest dysplasia | AD | |
Fibrochondrogenesis | AR | |
Fibrochondrogenesis | AD | |
Otospondylomegaepiphyseal dysplasia (OSMED) | AR | |
Achondrogenesis IB | AR | |
Atelosteogenesis II | AR | |
Diastrophic dysplasia | AR | |
Chondrodysplasia with congenital joint dslocations | AR | |
Dyssegmental dysplasia | AR | |
Dyssegmental dysplasia, Silverman-Handmaker type | AR | |
Dyssegmental dysplasia, Rolland Desbuquois type | AR | |
Otopalatodigital syndrome I and II | XLD | |
Osteodysplasty, Melnick-Needles | XLD | |
Atelosteogenesis types I and III | AD | |
Larsen syndrome | AD | |
Spondylo-carpal-tarsal dysplasia | AR | |
Serpentine fibula-polycystic kidney syndrome | AD | |
Metatopic dysplasia | AD | |
Chondroectodermal dysplasia (Ellis-van Creveld (EVC) | AR | |
Short-rib polydactyly syndrome I, II, III and IV including Asphxiating Thoracic Dystrophy | AR | |
Thoracolaryngeal dysplasia | AD | |
Cartilage-hair hypoplasia | AR | |
Metaphyseal dysplasia, Jansen type | AD | |
SEMD, short limb abnormal calcification type | AR | |
Achondrogenesis 1A | AR | |
Schneckenbecken dysplasia | AR | |
Opsismodysplasia | AR | |
Acromesomelic dysplasia, type Maroteaux | AR | |
Langer type (homozygoud dyschondrosteosis | pseudo-AR/XLD | |
Omodysplasia | AR | |
Robinow syndrome, recessive | AR | |
Robinow syndrome, dominant | AD | |
Campomelic dysplasia | AD | |
Stuve-Wiedemann dysplasia | AR | |
Bent bone dysplasia FGFR2 type | AD | |
Microcephalic osteodysplastic primordial dwarfism (MOPD1) | AR | |
Microcephalic osteodysplastic primordial dwarfism (MOPD2) | AR | |
Osteocraniostenosis | ||
Desbuquois dysplasia | AR | |
Pseudodiatrophic dysplasia | AR | |
CDP, X-linked dominant | XLD | |
Conradi-Hunermann type (CDPX2) | XLR | |
brachytelephalangic type (CDPX1) | XLD | |
CHILD syndrome | XLD | |
Greenberg dysplasia | AR | |
Rhizomelic CDP type 1 | AR | |
Rhizomelic CDP type 2 | AR | |
Rhizomelic CDP type 3 | AR | |
Bloomstrand dysplasia | AR | |
Desmosterolosis | AR | |
Caffey disease (infantile) | AD | |
Raine dysplasia | AR | |
Osteopetrosis (severe neonatal or infantile forms) | AR | |
Osteopetrosis (severe neonatal or infantile forms) | AR | |
Dysosteosclerosis | AR | |
Lenz-Majewski hyperostostic dysplasia | SP | |
Osteogenesis imperfecta, moderate, severe and perinatal lethal | AD | |
Osteogenesis imperfecta, moderate, severe and perinatal lethal | AR | |
Bruck syndrome | ||
Osteoporosis-pseudoglioma syndrome | AR | |
Cole-Carpenter dysplasia | SP | |
Hypophosphatasia, perinatal and infantile forms | AR |
AD –autosomal dominant type, AR- autosomal recessive, XLD- X-linked dominant, XLR- X-linked recessive, SP- supertype
Diastrophic dysplasia occurs predominantly among the Caucasian population [3, 8]. The prevalence of DTD is estimated at 1-1.3/100,000, and mainly has an AR type of inheritance. The disorder affects both males and females in equal numbers [4]. This pathology is widespread in Finland, occurring in about 1 in 30,000 newborns. In particular, 1-2% of the Finnish population are carriers of pathogenic variants of the
Frequency of occurrence of this disorder in our country is unknown. Several cases of
Mutation in the
Taking into the account the rareness of the disease, ethnic difference, and the lack of reporting about DTD disease course in adults, we present the phenotype description of 42-year-old woman from the west of Ukraine with diastrophic dysplasia and two pathogenic variants in the
We present a case of DTD in a 42-year-old Ukrainian woman. The patient’s stature is 110 cm with S-shaped deformation of the spine. The patient’s daughter applied to the Medical Genetic Center for advice on pregnancy planning and the possible risk of skeletal dysplasia for future children. The daughter is clinically healthy.
The anamnesis and result of examination of her mother with skeletal dysplasia is as follows: she has been patient from a physiological birth. Her birth weight was 4,200 kg. After birth, the newborn was diagnosed with severe asphyxia. The parents of the woman are somatically healthy, and they are not closely related. No cases of skeletal dysplasia in the family have been reported. The patient also had stridor nasal breathing at birth. The phenotype of the patient had the following features: the lower extremities were poorly stretched and tight to the body. The conclusion of the orthopedist during the examination was that the shortening of long (tubular) bones were manifested more on the lower extremities. At the age of 1 year the diagnosis was congenital dislocation of a hip, bilateral; arthrogryposis. At age of 21, she was diagnosed with a mixed form of chronic cholecystitis. At the age of 23, she was diagnosed with left ureter contraction, urolithiasis, chronic gastritis, kyphoscoliosis. At the age of 24, she was diagnosed with spondyloepiphyseal dysplasia, obsolete injury of the left shoulder. The woman was referred for consultation to the Institute of Traumatology and Orthopedics, where she was diagnosed with multiple skeletal bone deformities. They recommended to perform an MRI to assess skeletal bone damage. The MRI findings showed scoliosis (4th grade), osteochondrosis, spondyloarthritis of the spine. There were also protrusions of disks C3-C4, C4-C5, C5-C6, C6-C7, and L5-S1 (Figure 1). Intervertebral space contracted from L1 to L5 (Figure 1).
MRI findings of DD patient: Scoliosis (4th grade), osteochondrosis, spondyloarthritis of the spine. Protrusions of disks C3-C4, C4-C5, C5-C6, C6-C7, L5-S1
The patient has the skull of normal size with a disproportionately short skeleton, short lower extremities, brachydactylia, lack of interphalangeal creases, and hitchhiker thumb (abduced, located proximally) (Figures 2, 3, 4). The patient also has a vision defect, specifically myopia. Deviations in intellectual development were not observed. She has two healthy children born by caesarean section.
The phenotypic traits of DD patient: brachydactylia (short fingers), absence of flexion creases of the fingers, and proximally placed, abducted «hitchhiker thumb».
Due to the observed phenotype and skeletal deformities, the genetic testing of the panel genes involved in the etiology of skeletal disorders was performed by the next generation sequencing (NGS) method. The selected diagnostic test evaluates complete sequencing and deletion/duplication of 320 genes (Appendix 1) for variants, which are associated with genetic disorders that have phenotype of skeletal dysplasia. Two pathogenic variants in the
In
The
The identified in DD patient gene variants.
GENE | VARIANT | ZYGOSITY | VARIANT CLASSIFICATION |
---|---|---|---|
SLC26A2 | c.1020_1022del (p.Val341del) | heterozygous | PATHOGENIC |
SLC26A2 | c.1957T>A (p.Cys653Ser) | heterozygous | PATHOGENIC |
LTBP2 | c.3913G>C (p.Asp1305His) | heterozygous | Uncertain Significance |
TTC21B | c.3932G>A (p.Arg1311His) | heterozygous | Uncertain Significance |
Two pathogenic variants, c
Skeletal dysplasias belong to a genetically heterogeneous group of dysplasias, which may be caused by different mutations in more than 300 genes [19]. The main phenotypic presentation for those are growth disorders. The diagnosis of diastrophic dysplasia implies the conjunction of clinical, radiological, and histopathological symptoms. Establishing an accurate diagnosis is a complicated task, and the results of genetic testing play a key role here.
In the presented case, the 42-year-old woman was found to have
The parents of the patient are not available to identify the trans- or cis- position of two pathogenic variants on the chromosome. Two healthy descendants of our proband are healthy heterozygous carriers, confirming the location of the
Nutritional counseling to prevent obesity is important for such patients, as well as a multidisciplinary approach to their management [15, 16].
Future study shows the need to clarify the significance of different types of DTD among patients of Ukrainian origin with skeletal dysplasia symptoms and to estimate heterozygous carrier rates in the population. The results of the genetic testing and evaluating of the DTD-involved gene could be important for the selection of management and new treatment development.