Search

BACKGROUND: Split-hand/foot malformation (SHFM)-also known as ectrodactyly-is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1-6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved. METHODS: High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments. RESULTS: Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ~11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins. CONCLUSIONS: Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of non-penetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.

Introduction The clinical phenotype of the chromosome 2q31 deletion syndrome consists of limb anomalies ranging from monodactylous ectrodactyly, brachydactyly and syndactyly to camptodactyly. Additional internal organ anomalies—for example, heart defects, ocular anomalies—may be present. Hemizygosity for HOXD13 and EVX2 genes was thought to cause the observed skeletal defects. Recently, based on the phenotype of patients with overlapping 2q31 interstitial deletions, a new SHFM5 locus was proposed, proximal to the HOXD cluster, between EVX2 and marker D2S294. DLX1 and DLX2 haploinsufficiency was suggested as the most plausible explanation for the observed SHFM-like limb anomalies in these cases. Methods and results Five unique, interstitial 2q31 deletion patients were selected to further characterise the 2q31 region and to establish a genotype/phenotype correlation map. The size of the deletions was delineated with a chromosome 2 specific tiling path bacterial artificial chromosome (BAC) array. The clinical and molecular data for this group of patients were compared to others in the literature. A common locus for the observed skeletal anomalies, including the HOXD genes and surrounding regulatory sequences, was delineated. These results correlate with recently published studies in animal models. In addition, a critical region for the facial gestalt of the 2q31.1 microdeletion syndrome was delineated. Conclusions These results reinforce the hypothesis that the variable skeletal phenotype in 2q31 deletion patients is a result of hemizygosity for the HOXD genes and that the 2q31.1 microdeletion syndrome is a well defined and clinically recognisable phenotype.

Background: EEM syndrome is the rare association of ectodermal dysplasia, ectrodactyly, and macular dystrophy (OMIM 225280). Methods: We here demonstrate through molecular analysis that EEM is caused by distinct homozygous CDH3 mutations in two previously published families. Results: In family 1, a missense mutation (c.965A→T) causes a change of amino acid 322 from asparagine to isoleucine; this amino acid is located in a highly conserved motif likely to affect Ca2+ binding affecting specificity of the cell-cell binding function. In family 2, a homozygous frameshift deletion (c.829delG) introduces a truncated fusion protein with a premature stop codon at amino acid residue 295, expected to cause a non-functional protein lacking both its intracellular and membrane spanning domains and its extracellular cadherin repeats 3–5. Our mouse in situ expression data demonstrate that Cdh3 is expressed in the apical ectodermal ridge from E10.5 to E12.5, and later in the interdigital mesenchyme, a pattern compatible with the EEM phenotype. Furthermore, we discuss possible explanations for the phenotypic differences between EEM and congenital hypotrichosis with juvenile macular dystrophy (HJMD), which is also caused by CDH3 mutations. Conclusions: In summary, we have ascertained a third gene associated with ectrodactyly and have demonstrated a hitherto unrecognised role of CDH3 in shaping the human hand.

Item does not contain fulltext EEC syndrome is an autosomal dominant disorder with the cardinal signs of ectrodactyly, ectodermal dysplasia, and orofacial clefts. EEC syndrome has been linked to chromosome 3q27 and heterozygous p63 mutations were detected in unrelated EEC families. In addition, homozygous p63 null mice exhibit craniofacial abnormalities, limb truncations, and absence of epidermal appendages, such as hair follicles and tooth primordia. In this study, we screened 39 syndromic patients, including four with EEC syndrome, five with syndromes closely related to EEC syndrome, and 30 with other syndromic orofacial clefts and/or limb anomalies. We identified heterozygous p63 mutations in three unrelated cases of EEC syndrome, two Iowa white families and one sporadic case in a Filipino boy. One family is atypical for EEC and has features consistent with Hay-Wells syndrome. In this family, the mutation ablates a splice acceptor site and, in the other two, mutations produce amino acid substitutions, R280C and R304Q, which alter conserved DNA binding sites. Germline mosaicism was detected in the founder of the mutation in one case. These three cases show significant interfamilial and intrafamilial variability in expressivity. We also screened p63 in 62 patients with non-syndromic orofacial clefts, identifying an intronic single nucleotide polymorphism but finding no evidence of mutations that would explain even a subset of non-syndromic orofacial clefts. This study supports a common role for p63 in classical EEC syndrome, both familial and sporadic, but not in other related or non-syndromic forms of orofacial clefts.

The ectodermal dysplasias (EDs) are a large and complex nosological group of diseases, first described by Thurnam in 1848. In the last 10 years more than 170 different pathological clinical conditions have been recognised and defined as EDs, all sharing in common anomalies of the hair, teeth, nails, and sweat glands. Many are associated with anomalies in other organs and systems and, in some conditions, with mental retardation. The anomalies affecting the epidermis and epidermal appendages are extremely variable and clinical overlap is present among the majority of EDs. Most EDs are defined by particular clinical signs (for example, eyelid adhesion in AEC syndrome, ectrodactyly in EEC). To date, few causative genes have been identified for these diseases. We recently reviewed genes known to be responsible for EDs in light of their molecular and biological function and proposed a new approach to EDs, integrating both molecular-genetic data and corresponding clinical findings. Based on our previous report, we now propose a clinical-genetic classification of EDs, expand it to other entities in which no causative genes have been identified based on the phenotype, and speculate on possible candidate genes suggested by associated "non-ectodermal" features. Keywords: ectodermal dysplasia; clinical-functional correlation; epithelial-mesenchymal interaction; ectodermal structural proteins

Editor—The split hand/split foot malformation (SHFM, MIM 183600) is a central reduction defect of the hands and feet and occurs both as an isolated malformation and as part of several syndromes including the EEC syndrome (MIM 129900). We report on a 2 year old boy with SHFM associated with features of ectodermal hypoplasia, a submucous cleft palate, congenital vertical talus, malformations of the middle ear, profound sensorineural hearing loss resulting from Mondini dysplasia, and a de novo deletion of the paternal chromosome 7q21.1-q21.3. This patient with syndromic SHFM represents a case of atypical EEC syndrome, but also displays abnormalities previously not associated with SHFM or EEC syndrome. The classical features of the autosomal dominant inherited EEC syndrome are ectrodactyly, ectodermal dysplasia, and clefting of the lip/palate. In most patients, there are additional anomalies typically affecting the urogenital and lacrimal systems.1 2 Some patients also have dysmorphic facies, a tendency to infectious disease, endocrine disorders, and mental retardation. This phenotypic variability has become increasingly apparent over the last 15 years3 4 and numerous related and overlapping syndromes have been delineated by many investigators.5 In an attempt to clarify classification, major and minor criteria for the diagnosis of EEC syndrome have been elaborated.3 4 Dominant inheritance of EEC has been documented in several large multigenerational families.6 At least 15 patients have been reported to have cytogenetic abnormalities of chromosome 7q21.2-7q22.1, including nine patients with interstitial deletions.7-9 In addition, mutations in the gene encoding the transactivation factor p63 on chromosome 3q27 have been identified in familial and sporadic cases of EEC syndrome.10 A third locus was mapped to chromosome 19q,11 further delineating the genetic heterogeneity of this syndrome. The reason for the phenotypic heterogeneity in EEC syndrome patients with 7q abnormalities is unclear …

We report on a male patient and members of his family with additional material in chromosome 3. This derivative chromosome 3 was transmitted from his mother who had a complex rearrangement between chromosomes 2, 3, and 7. It was possible to delineate her chromosomal rearrangement by microdissection and reverse painting and to exclude these aberrations from being responsible for neonatal deaths and several abortions in this family. Two members of this family suffer from ectrodactyly or split hand/foot malformations (SHFM) of the feet which possibly correlates with the derivative chromosome 7 containing a breakpoint in the SHFM1 critical region involving several homeobox genes. Keywords: microdissection; CGH; SHFM; ectrodactyly

Harstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically. Although several causal genes of HPE and ectrodactyly have been identified, the genetic cause of Hartsfield syndrome remains unknown. We hypothesised that a single key developmental gene may underlie the co-occurrence of HPE and ectrodactyly., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Split hand/split foot malformation (SHSF) has been described in several patients associated with cytogenetically visible rearrangements involving chromosome 7q. Characterisation of these patients has led to localisation of an autosomal dominant form of SHSF to 7q21-22; the locus has been designated SHFM1. We describe a patient with a complex, apparently balanced cytogenetic rearrangement, including a translocation breakpoint at 7q21.3 near the DSS1 gene. In addition to ectrodactyly of all four limbs, the patient has congenital deafness, submucous cleft palate, microcephaly, and mental retardation. This patient represents an additional case of syndromic ectrodactyly related to the SHFM1 gene region, which may be responsible for both syndromic and non-syndromic ectrodactyly.

A family with the EEC syndrome is reported. Two sibs have the classical form of the condition with ectrodactyly, ectodermal dysplasia, and clefting. Their mother, however, has only minimal evidence, with preaxial polydactyly of the right hand and duplication of the terminal phalanx of the second toe of the left foot with 3/4 syndactyly. The dilemmas faced by the genetic counsellor are discussed in this variable autosomal dominant condition.

Ectrodactyly or split hand/foot malformation (SHFM) is a human limb malformation characterised by underdevelopment or absence of the central digital rays and variable fusion of the remaining digits (MIM 183600). This condition occurs in 1 in 8500–25 000 newborns1–4 and is usually inherited in an autosomal dominant manner, although a family with an X linked form has also been reported.5 At least five loci are responsible for this condition in humans: SHFM1 on 7q21.3-q22.1,6,7 SHFM2 on Xq26,5,8 SHFM3 on 10q24,9,10 SHFM4 on 3q27,11 and SHFM5 on 2q31.12,13 SHFM is clinically heterogeneous, presenting in either non-syndromic or syndromic forms. The non-syndromic form of SHFM can be isolated (type I) or associated with long bone deficiency (type II).14 The latter disorder has several names, including cleft hand with absent tibia and SHFM with long bone deficiency (SHFLD (MIM 119100)). Patients with SHFLD have SHFM in association with underdevelopment or absence of one or more long bones, most commonly the tibia.14–18 As with other forms of SHFM, the pattern of limb deficiency in SHFLD may be widely variable, even among the limbs of an affected subject. This condition preferentially affects males (M:F 1.6:1), right sided limbs, and lower limbs.16 Other skeletal findings in SHFLD include hypoplastic hallux, club foot, polydactyly, and bifurcation of the distal femur.15 Although ectodermal dysplasia19,20 and other findings have been seen in some patients with SHFLD, no consistent pattern of non-skeletal anomalies has been observed. The prototypical syndromic form of SHFM is the EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate) (MIM 129900).21 The EEC phenotype includes SHFM, orofacial clefts, and abnormalities of the skin, teeth, hair, nails, lacrimal ducts, and mammary glands.21 Interestingly, penetrance in SHFLD (66%) …

In this report we describe two families with variable manifestations of the EEC syndrome. The findings in these families confirm that no symptom is obligatory for the diagnosis of EEC syndrome. In the absence of cleft lip/palate, EEC patients have a characteristic facial morphology with maxillary hypoplasia, short philtrum, and broad nasal tip.

We report here a father and daughter with digital abnormalities, nasolacrimal duct obstruction, and variable alopecia. The father had a cleft lip and palate and the daughter had choanal atresia. We propose they both have the EEC syndrome and show the variable expressivity of this disorder. Choanal atresia has not been previously reported in this condition.

Two half sibs with bilateral complete cleft lip and complete cleft of the palate associated with ectrodactyly of the hands and feet, born to the same phenotypically normal mother, are reported. The younger of the two sibs also has dominantly inherited tremors (also referred to as essential heredofamilial tremors) as did her biological father. Possible genetic causes to explain the recurrence of the facial and limb malformations in the half sibs with additional central nervous system malformations in the younger sib are discussed.

Ectrodactyly of the feet has been reported only twice in association with trisomy 18 syndrome. A severe form of this anomaly, the first with published illustrative x rays, is described in a male infant with trisomy 18 syndrome. It is suggested that this may represent an extreme expression of the foot anomalies more commonly associated with this syndrome.

An infant is reported with a complete form of the ectrodactyly-ectodermal dysplasia clefting (EEC) syndrome, inherited from his mother, who has a partial expression of the condition, without clefting. This observation stresses the phenotypic variability of the EEC syndrome, which in most cases is inherited as an autosomal dominant with reduced penetrance.