How to Cite this Article: Lacombe D, Delrue M-A, Rooryck C, Morice-Picard F, Arveiler B, Maugey-Laulom B, Mundlos S, Toutain A, Chateil J-F. 2010. Brachydactyly type A1 with short humerus and associated skeletal features. Am J Med Genet Part A 152A:3016–3021.
Brachydactyly type A1 with short humerus and associated skeletal features†
Article first published online: 12 NOV 2010
Copyright © 2010 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 152A, Issue 12, pages 3016–3021, December 2010
How to Cite
Lacombe, D., Delrue, M.-A., Rooryck, C., Morice-Picard, F., Arveiler, B., Maugey-Laulom, B., Mundlos, S., Toutain, A. and Chateil, J.-F. (2010), Brachydactyly type A1 with short humerus and associated skeletal features. Am. J. Med. Genet., 152A: 3016–3021. doi: 10.1002/ajmg.a.33761
- Issue published online: 23 NOV 2010
- Article first published online: 12 NOV 2010
- Manuscript Accepted: 20 AUG 2010
- Manuscript Received: 29 MAR 2010
- short humerus;
- triphalangeal thumbs
We report on a three-generation family affected with an osteochondrodysplasia transmitted as an autosomal dominant trait. The phenotype consists of short humerus, curved radius with accessory ossification centre at the proximal third of ulna, variable short stature and brachydactyly, and has not been reported to the best of our knowledge. The brachydactyly falls into the brachydactyly A1 category (especially short 2nd, 4th, and 5th middle phalanges). A unique feature in one family member is triphalangeal thumbs. Vertebrae are normal. Mental development is normal and deafness is seen in some of the family members. A mutation was excluded by sequencing the entire coding regions of the IHH gene encoding the Indian Hedgehog protein and the GDF5 gene. This condition is a novel chondrodyplasia phenotype or possibly one end of the spectrum of the brachydactyly A1. © 2010 Wiley-Liss, Inc.
Brachydactylies (BD) are a group of inherited malformations of the digits classified by Bell 1951 into the five clinical types A, B, C, D, and E. Brachydactyly type A (BDA) is divided into three subtypes-A1, A2, and A3-in which the shortening of the extremities mainly involves the middle phalanges. The A1 type (BDA1) is characterized by shortness or absence of the middle phalanx of all digits in the hands and feet (brachymesophalangia), shortness of the proximal phalanx of the first digit, shortness of the metacarpals except for the first one, and in some cases, fusion of the middle and terminal phalanges. This trait is the first interpreted example of a human anomaly with mendelian autosomal dominant inheritance by Farabee 1903, and, as such, is cited in most genetic textbooks. BDA1 shows clinical variability both within and between families. Some BDA1 patients are described with short stature, short femur, malformed epiphyses, scoliosis, abnormal menisci, and clubfeet [Raff et al., 1998; Slavotinek and Donnai, 1998]. About half of the BDA1 families are due to mutations in the IHH (Indian Hedgehog) gene [Gao et al., 2001]. Genetic heterogeneity is recognized with a second gene locus mapped to chromosome 5p13.3-p13.2 [Yang et al., 2000] and a third locus suggested from the exclusion of chromosomes 2 and 5 regions in one BDA1 family [Kirkpatrick et al., 2003]. Recently mutations in GDF5 (Growth and Differentiation Factor 5) have been identified [Bulman et al., 2009]. We report on a three-generation BDA1 family without any IHH or GDF5 genes mutation and with particular skeletal features unreported to date.
The propositus was born at 39 weeks of gestation (WG) by cesarean, after a pregnancy marked by ultrasound identification of shortness of humeri (<3° centile), confirmed by skeletal study on 3D CT during the third trimester of pregnancy (Fig. 1). Birth parameters were normal (weight 3,000 g, height 50 cm, OFC 35.5 cm). Examination showed short arms, radial deviation of hands (Fig. 2a), and brachydactyly (Fig. 2b). X-rays demonstrated short humerus, bowing of radius, short ulna, short and broad metacarpals, short and broad 2nd to 5th middle phalanges (Fig. 3a), and short metatarsals. At age 7 months, height was 68 cm (0 SD) and weight 8.6 kg (0 SD). Mental development was normal. Audiogram was normal. No other feature was noticed. Growth was normal at age 19 months. He had a moderate limitation of prono-supination. X-rays showed several additional features. On the forearms, there was an aspect of “pseudarthrosis” at the proximal third of the ulna (Fig. 3b). On the hands, metacarpals remained short, but with a proximal accessory ossification centre; middle phalanges remained shortened, with tapering of distal phalanges. Plain film of the lower limbs demonstrated metaphysis irregularities on femurs and tibias (Fig. 3c). Cervical lordosis with basilar impression was present (Fig. 3d).
This was the first child of a 31-year mother. She underwent surgery for osteotomy of tibias at age 16 years because of genu valgum. Her height was 154 cm (−1.75 SD), weight was 51 kg (−1 SD), and OFC 56 cm (+1 SD). She had short arms, a radial angulation of forearms, limitation of prono-supination, and brachydactyly of hands and feet with short second phalanges of hands. X-rays during infancy showed short and broad humerus, abnormal incurvation of radius with short ulna and relative hypoplasia of the lateral condyle. At time of examination, X-rays showed short and broad 1st, 3rd, and 4th metacarpals, short 2nd, 4th, and 5th middle phalanges, slight tapering of the distal phalanx of digit 4, abnormal metacarpophalangeal joint in digit 5 (Fig. 4a), and short 1st, 4th and 5th metatarsals. Ulna was rather short, with radial luxation (Fig. 4b). Vertebrae were normal. She had normal hearing.
She had two brothers, one affected and one unaffected (see pedigree, Fig. 5). Height of the affected brother was 180 cm. He had the same skeletal phenotype including BDA1, short humeri, “pseudarthrosis-like aspect” of the proximal part of ulna demonstrated by X-rays during infancy (Fig. 6a), and radial bowing of the forearms. He had triphalangeal thumbs (Fig. 6b) and a bilateral mixed deafness with a threshold of 90 dB. He underwent surgery on the stapes at age 11 years.
The grandmother also had the same osseous dysplasia with brachydactyly, short 1st metacarpal and short middle phalanges (BDA1), short humerus, and incurvation of the radius with hypoplasia of the proximal part of the ulna. Her height was 155 cm (−1.5 SD) and she had a limitation of prono-supination. She had hearing loss since age 15 years. She also had a brother affected with the same chondrodysplasia (BDA1, short humerus, radial incurvation of the forearms; Fig. 7) and a height of 160 cm (−2.5 SD). Mental status was normal in all family members.
Peripheral blood samples were obtained from the propositus and his mother after informed signed consent. A mutation was excluded by sequencing of the entire coding regions of the IHH gene encoding the Indian Hedgehog protein and the GDF5 gene in the propositus and in his mother. CGH-array (Agilent 105 K) was normal in the mother. The microarray covered the GDF5 gene, but not IHH. However, heterozygous IHH mutations that cause BDA1 are not simple loss of function mutations and a heterozygous loss of function does not result in the disease. DNAs from other family members are not currently available for linkage analysis.
BDA1 is often reported as an isolated feature, but is probably associated, more often than reported, with other skeletal features in a more complex osteochondrodysplasia. In the original Farabee family, a skeletal survey was done 60 years later and already identified various bone and joints anomalies [Haws and McKusick, 1963]. BDA1 classically associates shortness or absence of the middle phalanx of all digits in the hands and feet, shortness of the proximal phalanx of the first digit, shortness of the metacarpals except for the first one, and in some cases fusion of the middle and terminal phalanges. There can be extreme variability in the limb anomalies within the same family. Some frequently reported hand features are reduction of size of all the hand bones, aplasia of the middle phalanges, radial clino/camptodactyly of the fourth and fifth fingers [Fitch, 1979], synostosis/symphalangism of fingers, hypermobile fingers, and missing distal finger creases. In BDA1, each middle phalanx may be proportionally shortened, or the second, fourth, and fifth phalanges may be more shortened than the middle three. There are some similarities with BDA4 that is defined by brachymesophalangy affecting mainly the 2nd and 5th digits. Clinodactyly of digit II [Stattin et al., 2009], and dysplasia of the carpals [McCready et al., 2002] are reported in BDA1. The feet generally show a similar pattern, but unaffected feet are described [Lodder et al., 2008]. We report on additional hand anomalies in this family including triphalangeal thumbs, demonstrating the extreme extremities anomalies segregating in the same family with other members affected with classical BDA1. We also observed the presence of an accessory ossification center at the proximal third of ulna, leading to a “pseudarthrosis” aspect before its fusion to the shaft.
Short stature is common [Haws and McKusick, 1963], but can be missing as in the reported family with affected members with normal or reduced stature. Shortness of the arm spans (−2 SD) is reported [Stattin et al., 2009], indicating short arms. The propositus of a recently reported family [Family 1, Byrnes et al., 2009] had short arms. The herein reported family has been identified via short humerus that is a feature not already indentified in BDA1. However, short femur is reported. Additional long bones features are sloping distal ends of radius and tibia, short or missing ulnar styloid process, short distal ulna regarding radius, elliptical head of the humerus, “mushroom” appearance of the femoral head [Temtamy and McKusick, 1978], and accessory carpal bones [Nissen, 1932]. Other reported bone findings are scoliosis [Raff et al., 1998], horizontal acetabulum, and glenoid hypoplasia. Slavotinek and Donnai 1998 reported a male infant from the Drinkwater 1915 family who showed more generalized skeletal anomalies including valgus deformity of both feet, a severe thoracolumbar scoliosis and subluxation of the lateral tibial condyle on the lateral femoral condyle. In our family, we also observed ossification abnormalities of long bones metaphysis of the lower limbs. Abnormal menisci of the knee leading to arthritis [Raff et al., 1998] and mild osteoarthritis of the carpo-metacarpo joints II, III, IV, and V [Stattin et al., 2009] are reported. Armour et al. 2002 described a family with nine affected individuals in three generations, stressing the phenotypic variability of BDA1. Metacarpophalangeal profiles can be useful to assess clinically atypical cases. Comparison of the main clinical features in BDA1 and in this family is provided in Table I. All these features argue to redefine BDA1 as a more generalized osteochondrodysplasia with extreme phenotype variability.
|Features||BDA1||BDA1+ (this report)|
Only two members of this family have hearing loss. Associated deafness with BDA1 is not mentioned in the literature. We cannot assume at this time that the hearing loss is associated with BDA1 or it maybe an independent feature not segregating with the disease. The IHH and GDF5 genes are not expressed in the developing ear or in the auditory system.
About half of the BDA1 families are due to a mutation in the IHH gene located on chromosome 2q35-q36. The hedgehog signaling family of proteins acts as key regulators for growth, patterning and morphogenesis of limbs during embryogenesis [Lai and Mitchell, 2005]. Indian Hedgehog is a central molecule for chondrocyte differentiation, development of joints, and bone formation [Mundlos, 2009]. The changes identified in IHH are missense mutations clustered in the amino-terminal signaling domain of the IHH protein, but no clear genotype–phenotype correlations are noted. Homozygous mutations in the IHH gene cause acrocapitofemoral dysplasia (ACFD), an autosomal recessive disorder with cone-shaped epiphyses in hands and hips [Hellemans et al., 2003]. The ACFD mutations seem to cluster on the other side of the molecule in comparison with BDA1. It is possible that BDA1 is caused by haploinsufficiency of the wild type protein [Gao et al., 2001]. Loss-of-function studies in the mouse demonstrate that Ihh is essential for chondrocyte proliferation and differentiation and for bone formation [St-Jacques et al., 1999]. In a mouse model with a BDA1 mutation (E95K) in Ihh, the mutation results in a gain of function due to impaired binding to the hedgehog inhibitor Hip and the receptor Patch [Gao et al., 2009]. Genetic heterogeneity is known in BDA1 with mutations in GDF5 and with a third locus on chromosome 5p13.3-p13.2 [Armour et al., 2002]. No mutations in the IHH and GDF5 genes were identified in our family and this is in favor of further genetic heterogeneity.
The phenotype of our family extends the clinical variation in BDA1 and stress the phenotype variability in this disorder. Reported skeletal features from literature BDA1 families argue for a complex osteochondrodysplasia predominating in the extremities and detailed bones X-rays will help to better define the BDA1 spectrum.
We thank the family for her cooperation and Dr. Geert Mortier (Ghent, Belgium) for his precious advice.
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