IllnessBrachydactyly, differential diagnosis

NGS +

Brachydactyly, the shortening of fingers and/or toes due to impaired development of the phalanges or metacarpals, occurs as an isolated malformation in a variety of different forms or in association with diseases of one or more other systems. The isolated brachydactylies are divided into 10 groups. Brachydactyly A is also called brachymesophalangy because the middle phalanges are shortened due to mutations e.g. in the IHH gene. In type A2, the middle phalanges are shortened, especially on the second fingers, resulting in radial deviation. Mutations in the BMPR1B, BMP2 and GDF5 genes cause this type. Type A3 is characterized by shortening of the middle phalanx of the 5.th finger and clinodactyly. In type A4, the middle phalanges of fingers 2 and 5 are shortened and clubfeet may occur. Type A5 shows shortened middle phalanges overall, and it is associated with nail dysplasia and bifid distal phalanges in the thumb and hallux. In type B, the middle phalanges are shortened or the terminal phalanges are absent. Type B is caused by ROR2 mutations, and it is also known as symbrachydactyly because of syndactyly, fusion of the phalanges and absence of the terminal phalanges. Type C can be particularly variable in its expression. Characteristically, the middle and proximal phalanges of the little finger are shortened, although the index and middle fingers may also be prominent. The proximal phalanx of the index finger may have marked ulnar deviation; short stature and clubfeet are associated features. This type is caused by GDF5 mutations. Type D is characterized by shortened, broad terminal phalanges of the thumbs and big toes, usually bilaterally. Mutations in the HOXD13 gene have been identified in some individuals. Type E is characterized by shortening of one or all of the metacarpals or metatarsals. The terminal phalanges are also often short, and the hands are frequently hyperextensible. Short stature or (mild generalized) spondyloepiphyseal changes occur as well. Individuals with an overlapping D/E phenotype may have HOXD13 or PTHLH mutations or GNAS inactivation. Furthermore, mutations in additional genes have been described for particularly rare types and syndromic brachydactyly. In families an autosomal dominant inheritance pattern has been identified in each type of isolated brachydactyly. The molecular diagnostic yield is unknown. Therefore, a negative DNA test result does not exclude the clinical diagnosis.

References: https://www.ncbi.nlm.nih.gov/books/NBK201366/

Brachydactyly, Elsevier 2017, https://doi.org/10.1016/B978-0-12-809633-8.06153-7

• Allelic: Acrocapitofemoral dysplasia (IHH)
• Allelic: Acromesomelic dysplasia 2A (GDF5)
• Allelic: Acromesomelic dysplasia 2B (GDF5)
• Allelic: Acromesomelic dysplasia 2C, Hunter-Thompson type (GDF5)
• Allelic: Acromesomelic dysplasia 3 (BMPR1B)
• Allelic: Albright hereditary osteodystrophy type 3 [panelapp] (HDAC4)
• Allelic: Albright hereditary osteodystrophy-like syndrome [panelapp] (HDAC4)
• Allelic: Aortic valve disease 1 (NOTCH1)
• Allelic: Avascular necrosis of femoral head, primary, 2 (TRPV4)
• Allelic: Brachyolmia type 3 (TRPV4)
• Allelic: Chromosome 2q37 deletion syndrome (HDAC4)
• Allelic: Cleidocranial dysplasia, forme fruste, dental anomalies only (RUNX2)
• Allelic: HFE hemochromatosis, modifier of (BMP2)
• Allelic: Hereditary motor + sensory neuropathy, type IIc (TRPV4)
• Allelic: Metatropic dysplasia (TRPV4)
• Allelic: Multiple synostoses syndrome 1 (NOG)
• Allelic: Multiple synostoses syndrome 2 (GDF5)
• Allelic: Neuronopathy, distal hereditary motor, type VIII (TRPV4)
• Allelic: Osteoarthritis-5 (GDF5)
• Allelic: Parastremmatic dwarfism (TRPV4)
• Allelic: Robinow syndrome, AR (ROR2)
• Allelic: SED, Maroteaux type (TRPV4)
• Allelic: Scapuloperoneal spinal muscular atrophy (TRPV4)
• Allelic: Sodium serum level QTL 1 (TRPV4)
• Allelic: Spinal muscular atrophy with progressive myoclonic epilepsy (ASAH1)
• Allelic: Spondylometaphyseal dysplasia, Kozlowski type (TRPV4)
• Allelic: Stapes ankylosis with broad thumbs + toes (NOG)
• Allelic: Symphalangism, proximal, 1A (NOG)
• Allelic: Symphalangism, proximal, 1B (GDF5)
• Allelic: Syndactyly, type V (HOXD13)
• Allelic: Synpolydactyly 1 (HOXD13)
• Allelic: Tarsal-carpal coalition syndrome (NOG)
• Adams-Oliver syndrome 5 (NOTCH1)
• Brachydactyly, type A1 (IHH)
• Brachydactyly, type A1, C (GDF5)
• Brachydactyly, type A1, D (BMPR1B)
• Brachydactyly, type A2 (BMP2)
• Brachydactyly, type A2 (BMPR1B)
• Brachydactyly, type A2 (GDF5)
• Brachydactyly, type B1 (ROR2)
• Brachydactyly, type B2 (NOG)
• Brachydactyly, type C (GDF5)
• Brachydactyly, type D (HOXD13)
• Brachydactyly, type E (HOXD13)
• Brachydactyly, type E2 (PTHLH)
• Brachydactyly-intellectual disability (HDAC4)
• Brachydactyly-syndactyly syndrome (HOXD13)
• Cleidocranial dysplasia (RUNX2)
• Cleidocranial dysplasia, forme fruste, with brachydactyly (RUNX2)
• Clubfoot, congenital, +/- deficiency of long bones +/or mirror-image polydactyly (PITX1)
• Cutis laxa, AR, type IIE (LTBP1)
• Digital arthropathy-brachydactyly, familial (TRPV4)
• Farber lipogranulomatosis (ASAH1)
• Hypertension + brachydactyly syndrome (PDE3A)
• Hypophosphatemic rickets, AR (DMP1)
• Liebenberg syndrome (PITX1)
• Metaphyseal dysplasia with maxillary hypoplasia with/-out brachydactyly (RUNX2)
• Short stature, brachydactyly, intellectual developmental disability + seizures (PRMT7)
• Short stature, facial dysmorphism, skeletal anomalies with/-out cardiac anomalies 1 (BMP2)
• Temtamy preaxial brachydactyly syndrome (CHSY1)