Donald Basel

Split-Hand/Split-Foot Malformation Is Caused by Mutations in the p63 Gene on 3q27

Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac). Results of recent studies have shown that, in heterozygous Dac embryos, the central segment of the apical ectodermal ridge (AER) degenerates, leaving the anterior and posterior segments intact; this finding suggests that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM. Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER. Two missense mutations, 724A-->G, which predicts amino acid substitution K194E, and 982T-->C, which predicts amino acid substitution R280C, were identified in exons 5 and 7, respectively, of the p63 gene in two families with SHFM. Two additional mutations (279R-->H and 304R-->Q) were identified in families with EEC (ectrodactyly, ectodermal dysplasia, and facial cleft) syndrome. All four mutations are found in exons that fall within the DNA-binding domain of p63. The two amino acids mutated in the families with SHFM appear to be primarily involved in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with the DNA.

Osteogenesis imperfecta: Recent findings shed new light on this once well-understood condition

Abstract. Osteogenesis imperfecta is a systemic heritable disorder of connective tissue whose cardinal manifestation is bone fragility. In approximately 90% of individuals with osteogenesis imperfecta, mutations in either of the genes encoding the pro-α1 or pro-α2 chains of type I collagen (COL1A1 or COL1A2) can be identified. Of those without collagen mutations, a number of them will have mutations involving the enzyme complex responsible for posttranslational hydroxylation of the position 3 proline residue of COL1A1. Two of the genes encoding proteins involved in that enzyme complex, LEPRE1 and cartilage-associated protein, when mutated have been shown to cause autosomal recessive osteogenesis imperfecta, which has a moderate to severe clinical phenotype, often indistinguishable from osteogenesis imperfecta types II or III. Mutations in COL1A1 or COL1A2 which result in an abnormal protein still capable of forming a triple helix cause a more severe phenotype than mutations that lead to decreased collagen production as a result of the dominant negative effect mediated by continuous protein turnover. The current standard of care includes a multidisciplinary approach with surgical intervention when necessary, proactive physiotherapy, and consideration for the use of bisphosphonates all in attempts to improve quality of life.

Mutations in LAMA1 Cause Cerebellar Dysplasia and Cysts with and without Retinal Dystrophy

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes.

Exome sequencing positively identified relevant alterations in more than half of cases with an indication of prenatal ultrasound anomalies

Exome sequencing is a successful option for diagnosing individuals with previously uncharacterized genetic conditions, however little has been reported regarding its utility in a prenatal setting. The goal of this study is to describe the results from a cohort of fetuses for which exome sequencing was performed.

Distal limb malformations: underlying mechanisms and clinical associations

Congenital malformations of the extremities are conspicuous and have been described through the ages. Over the past decade, a wealth of knowledge has been generated regarding the genetic regulation of limb development and the underlying molecular mechanisms. Recent studies have identified several of the signaling molecules, growth factors, and transcriptional regulators involved in the initiation and maintenance of the apical ectodermal ridge (AER) as well as the molecular markers defining the three axes of the developing limb. Studies of abnormal murine phenotypes have uncovered the role played by genes such as p63 and Dactylin in the maintenance of AER activity. These phenotypes resemble human malformations and in this review we describe the underlying mechanisms and clinical associations of split hand/foot malformation and ectrodactyly–ectodermal dysplasia–cleft lip/palate syndrome, which have both been associated with mutations in the p63 gene.

The expanding panorama of split hand foot malformation

The split hand/foot malformation is a developmental defect of the extremities resulting from errors in the initiation and maintenance of the apical ectodermal ridge. The phenotype is genetically heterogeneous, and it can be identified either as an isolated phenotypic manifestation or as a constituent component of a malformation syndrome. This overview describes the clinical phenotype, related animal models, and the evolving genetic heterogeneity of the malformation.

Split hand foot malformation is associated with a reduced level of Dactylin gene expression

Split hand foot malformation (SHFM) is a congenital limb malformation presenting with a median cleft of the hand and/or foot, syndactyly and polydactyly. SHFM is genetically heterogeneous with four loci mapped to date. Murine Dactylaplasia (Dac) is phenotypically similar, and it has been mapped to a syntenic region of 10q24, where SHFM3 has been localized. Structural alterations of the gene‐encoding dactylin, a constituent of the ubiquitinization pathway, leading to reduced levels of transcript have been identified in Dac. Here, we report a significant decrease of Dactylin transcript in several individuals affected by SHFM. This observation supports a central role for dactylin in the pathogenesis of SHFM.

Tibial aplasia--VACTERL association, a new syndrome?

We report on a male infant, born to nonconsanguineous parents, with a vertebral anomaly, cardiac defect, tracheo-oesophageal fistula and hypospadias (VACTERL association) together with bilateral tibial aplasia. This pattern of abnormalities appears to represent a unique syndrome.

Association of Piebaldism, Multiple Café-au-lait Macules, and Intertriginous Freckling: Clinical Evidence of a Common Pathway between KIT and Sprouty-Related, Ena/Vasodilator-Stimulated Phosphoprotein Homology-1 Domain Containing Protein 1 (SPRED1)

Abstract:  Piebaldism is a rare genodermatosis caused by KIT mutations. We report the case of a 5‐year‐old boy who had the white forelock and leukoderma of piebaldism, but the presence of many café‐au‐lait macules and axillary and inguinal freckling complicated the diagnosis. Patients with similar cutaneous findings have been previously reported, and their disorder has been attributed to an overlap of piebaldism and neurofibromatosis type 1. Legius syndrome is a recently described syndrome caused by Sprouty‐related, Ena/vasodilator‐stimulated phosphoprotein homology‐1 domain containing protein 1 (SPRED1) mutations that also has multiple café‐au‐lait macules and intertriginous freckling. Based on our current understanding of KIT and SPRED1 protein interactions, we propose that café‐au‐lait macules and freckling may be seen in some patients with piebaldism and does not necessarily represent coexistence of neurofibromatosis type 1.

Adaptive Behavior in Young Children with Neurofibromatosis Type 1

Neurofibromatosis-1 is the most common single gene disorder affecting 1 in 3000. In children, it is associated not only with physical features but also with attention and learning problems. Research has identified a downward shift in intellectual functioning as well, but to date, there are no published studies about the everyday adaptive behavior of children with NF1. In this study, parental reports of adaptive behavior of 61 children with NF1 ages 3 through 8 were compared to an unaffected contrast group (n = 55) that comprised siblings and community members. Significant group differences in adaptive skills were evident and were largely related to group differences in intellectual functioning. In a subsample of children with average-range intellectual functioning, group differences in parent-reported motor skills were apparent even after controlling statistically for group differences in intellectual functioning. The implications of the findings for the care of children with NF1 are discussed.