Dorsal Dimelia Research Articles

Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator.

Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks1, but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.

Distal Dorsal Dimelia: A Disturbance of Dorsal-Ventral Digit Development

Congenital palmar nail (distal dorsal dimelia [dDD]) of the hand is a rare malformation most commonly affecting the little finger. The purpose of this report was to review the features and associations of this rare disorder and discuss the suspected underlying etiology in light of our current understanding of developmental biology. In this retrospective cohort study from 3 practices, we describe our collective experience and review the reported literature on this disorder both as an isolated condition and in conjunction with other anomalies. We examined 15 fingers with dDD, 5 of which involved little fingers. We also found dDD in 6 cases with radial polydactyly (preaxial polydactyl type II [PPD2]) and in 1 case of cleft hand involving digits adjacent to the clefted web space (the index and middle fingers). Cases of little finger dDD were also associated with prominent clefting of the adjacent web space in 4 of 5 cases. All cases had stiffness of the interphalangeal joints and loss of palmar creases consistent with dorsalization of the palmar aspect of the digit. When combined with 63 fingers reported in the literature with dDD, 3 patterns were evident. The most common form occurred in little fingers (n= 50; 64%; dDDu). The next most common form was reported in association with cleft hands (n= 16; 21%; dDDc). Radial digits in association with either radial polydactyly (PPD2) or radial longitudinal deficiency were also susceptible to dDD (n= 12; 15%; dDDr). Congenital dDD is a disturbance of terminal dorsal-ventral digit patterning. The distribution of this condition with little fingers, clefting, and altered radial digit formation (PPD2 or radial longitudinal deficiency), as well as recent genetic and animal studies, suggests that dDD and altered dorsal-ventral patterning are linked to abnormal apical ectodermal ridge boundary formation. Diagnostic IV.

Concurrent dorsal dimelia in 160 consecutive patients with congenital anomalies of the hands and feet

This study was designed to investigate the prevalence of dorsal dimelia in a series of 160 consecutive patients with congenital anomalies of the hands and feet, and to investigate the distribution of dorsal dimelia and the concurrent anomalies. Five cases (3.1%) showed evidence of dorsal dimelia and the distribution of dorsal dimelia was similar to the distribution of concurrent anomalies in all five cases. Another 11 cases of concurrent dorsal dimelia with other congenital anomalies have been reported previously with a positive match in the distributions in all cases. This similarity in the distribution in all 16 reported cases (including the five cases in the current study) is statistically significant. It is concluded that dorsal dimelia in humans is not as rare as it is generally thought to be, and that it may be viewed as an error of dorso-ventral patterning, which occurs in the same distribution as other concurrent anomalies.

Dorsal Dimelia of the Fourth Toe in a Patient With Incontinentia Pigmenti

Development of a second nail plate on either the plantar or palmar surface of a digit, known as a double nail, is an extremely rare malformation. When dorsalization of the plantar skin is also present, the condition is referred to as dorsal dimelia. Additional findings associated with dorsal dimelia may include loss of flexion creases with absent flexion at the interphalangeal joints and tapering of the distal phalanx seen on radiography. We report herein a case of an affected toe in a patient with incontinentia pigmenti (IP).

Classification of dorsal and ventral dimelia in humans

Dorsal dimelia (appearance of dorsal structures on the palmar aspect of the hand) and ventral dimelia (appearance of palmar structures on the dorsal aspect of the hand) are rare congenital hand malformations that occur due to errors of the dorso-ventral axis of development of the limb. The current literature includes numerous cases and there is now sufficient basic science/genetics research on the topic so that a classification of dorsal/ventral dimelia could be proposed. Dorsal dimelia is subclassified into two types: distal (dorsalization of the digits ± distal palm) and proximal (dorsalization of the proximal palm only) types. Ventral dimelia is classified into three types (mild, moderate, and severe) according to the degree of ventralization. The classification is supported by the genetic basis of each subtype.

Fanconi Anemia With Concurrent Thumb Polydactyly and Dorsal Dimelia

Fanconi anemia is known to be associated with radial ray deficiency (thumb and radius hypoplasia), and its embryological basis remains to be poorly understood. We describe a rare case of Fanconi anemia with concurrent thumb polydactyly and dorsal dimelia. The embryological basis of limb abnormalities in Fanconi anemia patients is thought to be based on the complex interactions between the apical ectodermal ridge (where Fanconi anemia genes are expressed) and both the mesoderm (where Spalt-like 4 (SALL4) and Sonic hedgehog (SHH) are located and which are responsible for radial ray deficiency, thumb polydactyly, and triphalangism) and the dorsoventral axis (an error in that axis leads to dorsal dimelia).

Dorsal Dimelia of the Index Finger in a Patient With Absent Thumb and Radial Club Hand

Dorsal dimelia is a rare form of duplication along the dorsoventral axis as opposed to polydactyly and hyperphalangism, which are duplications along the radioulnar and proximodistal axes, respectively. All previous cases of dorsal dimelia involved the ulnar digits. We report the first human case of dorsal dimelia of a radial digit (index finger) in a patient with absent thumb and radial club hand. Associated anomalies of previously reported cases of dorsal dimelia are reviewed and their pathogenesis is discussed.

Dorsal dimelia of a thumb

Dorsal dimelia (congenital palmar polyonychia) of the hand is defined as the presence of an ectopic palmar nail at the tip of the finger with evidence of dorsalisation of the palmar skin. All reported human cases involved the little or ring fingers and none of the affected digits were subjected to detailed examination. We report the first human case of dorsal dimelia involving a thumb, and provide gross and histological examination of the affected digit. We also review the embryology of this rare deformity and previously reported cases.

Dorsal Dimelia: Report of Two Cases With an Emphasis On the Variation of Phenotypic Expression and a Search for Candidate Causative Genes

Dorsal dimelia is a form of duplication along the dorsoventral axis of the developing limb. Previous authors reporting on this rare entity have stated that the essential feature of the deformity is the presence of double or circumferential nail at the tip of the finger and that the aetiology is probably related to a mutation of Engrailed-1 (En-1). In this paper we report on two cases to demonstrate that the deformity in humans may be fully or partially expressed, with or without the double nail deformity, respectively. We also reviewed reported cases in humans and experimental animals and searched our two cases for candidate causative genes within the En-1 pathway.

Dorsal Dimelia in Patau Syndrome: A Case Report

We present a case of a child with Patau syndrome that exhibits features consistent with congenital palmar nail syndrome. The literature is reviewed and evidence presented to demonstrate that this is a defect in the dorso-ventral patterning of the limb and thus a form of dorsal dimelia. In order to differentiate this from other instances of ectopic nail tissue we suggest congenital palmar nail syndrome should be more specifically defined as duplicated nails, absent flexion creases, non-glabrous skin on the palmar surface, reduced movement at the interphalangeal joints and hypoplastic terminal phalanges.