Brachydactyly E: isolated or as a feature of a syndrome

Abstract

Brachydactyly (BD) refers to the shortening of the hands, feet or both. There are different types of BD; among them, type E (BDE) is a rare type that can present as an isolated feature or as part of more complex syndromes, such as: pseudohypopthyroidism (PHP), hypertension with BD or Bilginturan BD (HTNB), BD with mental retardation (BDMR) or BDE with short stature, PTHLH type. Each syndrome has characteristic patterns of skeletal involvement. However, brachydactyly is not a constant feature and shows a high degree of phenotypic variability. In addition, there are other syndromes that can be misdiagnosed as brachydactyly type E, some of which will also be discussed. The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis. As in our experience many of these patients are recruited at Endocrinology and/or Pediatric Endocrinology Services due to their short stature, we have focused the algorithm in those steps that could mainly help these professionals.

Figure 1

Radiographs of hands (A) and feet (B) of a non adult individual with heterozygous mutation in HOXD13(OMIM#113300) (courtesy of Dr. Aleksander Jamsheer). Shortening and widening of IV and V metacarpals are more evident in right; I, IV and V distal brachyphalangy, and mild clynodactyly of the distal phalanx of II and V, in left hand. In the feet, note asymmetrical shortening of the metatarsals: in right feet II, III, IV are shortened and in the left one, only III and IV. Note also, the clynodactyly of right hallux.

Figure 2

Hand of a patient with pseudohypopthyroidism type Ia (OMIM#103580). Note the shortening of first metacarpal and proximal phalanx of the thumb and more severe shortening of metacarpals IV and V (courtesy of Dr. Beatriz Garcia-Cuartero).

Figure 3

Hand of a patient with acrodysostosis and multihormonal resistance (OMIM#101800). Severe and generalized brachydactyly, through very short and broad tubular bones, including ulna can be observed. Metacarpals II-V are proximally pointed and cone-shaped proximal phalangeal epiphyses are prematurely fused. The general appearance of the hand is bulky and stocky (courtesy of Prof. Dr. Jesús Argente).

Figure 4

Hands of a patient with Bilginturan BD or HTNB (OMIM%112410). Metacarpals are short (specially II-V) with globular ends, irregular articular surfaces and cup deformity in the epiphysis of the proximal and medial phalanges. All the phalanges of the hands are also shortened, but the proximal and middle phalanges of the III and IV digits are relatively normal (courtesy of Dr. Sylvia Bähring and Dr. Okan Toka, unpublished case).

Figure 5

Right hand in a non adult individual with heterozygous mutation in PTHLH. Severe shortening of IV and V metacarpals is clearly observed (courtesy of Dr. Cécile Teinturier-Thomas, personal collection; Dr. Caroline Silve, molecular diagnosis, unpublished case).

Figure 6

Hands of a patient with tricho-rhino-phalangeal syndrome I (OMIM#190350). The patient presents asymmetrical brachydactyly; metacarpals III and V are shortened on the left hand and IV and V on the right. Further, middle phalanges are shortened and cone-shaped epiphyses are shown with the typical outcarving and deformation (arrows) (courtesy of Dr. Sharona Azriel, unpublished case).

Figure 7

Hand (A) and radius (B) of a patient with Turner syndrome. It can be observed the ulnar and palmar slant of the radial articular surfaces, with a triangular appearance of the distal radial epiphysis and slight shortening of the IV metacarpal; the radius is short and bowed.

Figure 8

Proposed clinical algorithm to suggest the most probable genetic diagnosis. Features in brackets are not always present in the syndromes. BDE Brachydactyly type E, PHP-Ia Pseudohypopthyroidism type Ia, MLPA Multiplex ligation-dependent probe amplification, MS-MLPA Methylation specific-MLPA.