Abstract
Brachydactyly type A1 (BDA1) is characterized by short middle phalanges. We report the case of a child with a severe form of BDA1 with complete absence of the middle phalanges of all extremities. He had c.298G > A (p.D100N) mutation in IHH gene.
Keywords: brachydactyly type A, GDF5, IHH
Introduction
Brachydactyly (BD) without extraskeletal manifestations is a group of skeletal disorders characterized by abnormal development of the metacarpals, metatarsals, and/or phalanges. BD was originally classified into five types (A–E) by Bell. 1 The condition was again reclassified by Fitch, Temtamy, and McKusick. 2 3 BD type A1 (BDA1) is characterized by a spectrum of phenotypes ranging from severe shortening or absence of the middle phalanges of the fingers and toes to the fusion of the middle and distal phalanges. Milder phenotypes involve hypoplasia of the middle phalanges in digits 2 and 5. Until now, mutations in IHH and GDF5 genes have been reported to cause BDA1. 4 5 6 In this article, we report a severe case of BDA1 with missing phalanges in digits 2 to 5 of the hands and feet.
Case Report
A 5-month-old male presented with BD and joint laxity of the hands and feet ( Fig. 1A–H ). He was the only child born to nonconsanguineous asymptomatic parents. There was no significant family history. He had a birth weight of 2.5 kg (standard deviation: –2). Initial examination was performed at the age of 5 months, reporting normal growth parameters with a length of 68 cm, head circumference of 42.5 cm, and weight of 6.5 kg. He was noted to have bilateral single interphalangeal joint creases. Radiographs of both his hands and feet revealed the absence of the middle phalanges of digits 2 to 5 ( Fig. 2A–D ). There were no other skeletal abnormalities or systemic anomalies. The study protocol was approved by the institutional ethics committee at Kasturba Hospital in Manipal, and written informed consent was obtained from the participating patient. IHH and GDF5 were sequenced from the blood samples obtained from the child. A known pathogenic variant, c.298G > A (p.D100N), in exon 1 of IHH gene was identified. 7 Sanger sequencing of parents did not reveal this variant, suggesting a de novo occurrence of the mutation.
Fig. 1.
( A–H ) Photographs of hands and feet show brachydactyly. He has a single digital crease ( A,B ) and sandal gap deformity ( E,F ). Otherwise he is noted to have unremarkable extremities.
Fig. 2.
Radiographs of the hands and feet show brachydactyly and missing middle phalanges of digits 2 to 5 in both the hands ( A,B ) and feet ( C,D ).
Discussion
The locus 2q35-q37 responsible for BDA1 was identified in two large Chinese families. IHH gene within this locus was unraveled as one of the cause of BDA1. 4 5 Since then, eight mutations have been identified in 13 families. 5 7 8 9 10 11 12 13 14 Clinical features of patients with mutations in IHH gene are tabulated in Table 1 . To date, only 13 families (88 affected individuals) with BD have been reported with mutations in IHH gene ( Table 1 ). The spectrum of severity associated with the variant c.298G > A (p.D100N) in IHH gene observed in this case and those previously reported cases could be due to variable expression.
Table 1. Clinical features of patients with mutations in IHH gene .
| Serial no. | Total no. of family | No. of cases | Common features | Additional features | Mutation | Reference |
|---|---|---|---|---|---|---|
| 1 | 1 | 10 | Short middle phalanges of F2–F4; fused middle and terminal phalanges of F5 | − | c.461C > T (p.Thr154Ile) |
Liu et al 8 |
| 2 | 2 | 5 | Bilateral dysplasia of the carpals, metacarpals, and phalanges; absence of middle phalanges in F2, F3, and F5 | Spurs on the trapezium; musculoskeletal problems such as pain in hip and knee | c.298G > A (p.Asp100Asn) | McCready et al 7 |
| 3 | Broad hands and feet with hypoplasia or absence of middle phalanges in F2–F5 and short proximal phalanx of F1 | Bilateral valgus deformity, double scoliosis, irregular femur, nystagmus, squint, developmental delay | ||||
| 3 | 3 | 18 | Variable phenotype of middle phalanges including absence of all middle phalanges or absence of middle phalanges F2, F4, and F5, or absence of middle phalanx F5 | − | c.283G > A (p.Glu95Lys) | Yang et al, 4 Gao et al 5 |
| 15 | Absence of middle phalanges; short middle phalanges in F2, F3, and F4; thin shafts and broad epiphyses in the metacarpals and proximal phalanges; short proximal phalanx of F1 | Clinodactyly | c.391G > A (p.Glu131Lys) | |||
| 5 | Clinical phenotype of BDA1 | − | c.300C > A (p.Asp100Glu) | |||
| 4 | 1 | 14 | Broad and shortened digits; variable phenotypes of middle phalanges and metacarpal among affected individuals | − | c.298G > A (p.Asp100Asn) | Zhu et al 10 |
| 5 | 1 | 3 | Mild BDA1; broad and short digit of F1–F5 | Absence or hypoplasia of the styloid process ulna | c.298G > A (p.Asp100Asn) | Giordano et al 12 |
| 6 | 4 | 2 | Short middle phalanges, prominent in F2 and F5; short proximal phalanx of F1 | Short arms, restricted dorsiflexion of the feet, tarsal coalition | c.383G > A (p.Arg128Gln) | Byrnes et al 13 |
| 3 | Short middle phalanges | Distal symphalangism, scoliosis, clubfoot | c.389C > A (p.Thr130Asn) | |||
| 2 | Short proximal and distal phalanges in F1 | − | c.391G > A (p.Glu131Lys) | |||
| 7 | Absence of middle phalanges in F2–F5 in both hands and feet, short proximal phalanx in F1, syndactyly of F2 and F3 | Nonspecific knee and hip problems, hallux vulga, absence of lateral incisors | c.298G > A (p.Asp100Asn) | |||
| 7 | 1 | 1 | No details described | − | c.284A > G (p.Glu95Gly) | Kirkpatrick et al 9 |
| 8 | 1 | 1 | Absence of middle phalanges in F2–F5 in both hands and feet | − | c.298G > A (p.Asp100Asn) | Present case |
Note: Hyphen indicates absence of data.
The most common phenotype observed is the absence of or short middle phalanges of digits. In some cases, additional features such as syndactyly, clinodactyly, spurs on the carpal bones, scoliosis, club foot, nystagmus, squinting, and developmental delay are also observed. In a French-Canadian family with BDA1, linkage analysis to 5p13.3–13.2 and sequence analysis of IHH gene did not reveal any pathogenic variation. 9 Mutation analysis in the patients of this family revealed a variant in GDF5 gene. 6 Mutations in GDF5 gene are known to cause BDA2 (OMIM: 112600) and BDC (OMIM: 615072). All of the preceding data suggests the presence of phenotypic heterogeneity and genetic heterogeneity in BDA1.
We report a severe form of BDA1 with missing middle phalanges of all digits in both the hands and feet. Reporting this c.298G > A (p.D100N) mutation in the family further validates the pathogenicity of the variant and indicates this is the most common variant in IHH gene. This report adds the phenotype of an infant to the literature.
Acknowledgment
The authors would like to thank the family for cooperating in this study, and the Department of Science and Technology, Government of India, for funding the project titled “Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development” (SB/SO/HS/005/2014).
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