A classification system for split-hand/ foot malformation (SHFM): A proposal based on 3 pedigrees with WNT10B mutations.

SHFM6 (OMIM 225300) is caused by WNT10B pathogenic variants (12q13.12). It is one of the rarest forms of SHFM; with only seven pathogenic variants described in the world literature. Furthermore, it has not been determined if SHFM6 has specific phenotypic characteristics. In this paper, we present a case series of three unrelated families with SHFM6 caused by three novel WNT10B pathogenic variants. The index patient of the first family was homozygous for the nonsense variant c.676C > T (p.Arg226*) in the WNT10B gene. The index case of the second family had a homozygous splice variant c.338-1G > C in the WNT10B gene. Finally, the index case of the third family carried two different variants in the WNT10B gene: A nonsense variant (p.Arg226*), and a missense variant (p.Gln86Pro). The latter represents the first compound heterozygous pathogenic variant related to SHFM6. We also offer a classification system for the hand/foot defects to illustrate the specific phenotypic characteristics of SHFM6. Based on this classification and a review of all previously reported cases, we demonstrate that SHFM6 caused by WNT10B pathogenic variants have the following characteristics: more severe feet defects (compared to the hand defects), polydactyly, severe flexion digital contractures, and phalangeal dysplasia.

Spectrum of congenital anomalies among VACTERL cases: a EUROCAT population-based study.

BACKGROUND: The VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association is the non-random occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies. Diagnosing VACTERL patients is difficult, as many disorders have multiple features in common with VACTERL. The aims of this study were to clearly outline component features, describe the phenotypic spectrum among the largest group of VACTERL patients thus far reported, and to identify phenotypically similar subtypes. METHODS: A case-only study was performed assessing data on 501 cases recorded with VACTERL in the JRC-EUROCAT (Joint Research Centre-European Surveillance of Congenital Anomalies) central database (birth years: 1980-2015). We differentiated between major and minor VACTERL features and anomalies outside the VACTERL spectrum to create a clear definition of VACTERL. RESULTS: In total, 397 cases (79%) fulfilled our VACTERL diagnostic criteria. The most commonly observed major VACTERL features were anorectal malformations and esophageal atresia/tracheo-esophageal fistula (both occurring in 62% of VACTERL cases), followed by cardiac (57%), renal (51%), vertebral (33%), and limb anomalies (25%), in every possible combination. Three VACTERL subtypes were defined: STRICT-VACTERL, VACTERL-LIKE, and VACTERL-PLUS, based on severity and presence of additional congenital anomalies. CONCLUSION: The clearly defined VACTERL component features and the VACTERL subtypes introduced will improve both clinical practice and etiologic research.

Insights into the pathogenesis and treatment of split/hand foot malformation (cleft hand/foot).

Cleft hand or split hand foot malformation is a sequence of phenotypes, from a minor shortening of the central digit to a complete absence of the third ray and in the most severe cases, absence of two, three or four rays. It is a rare but spectacular presentation usually involving both hands and feet. Inheritance is mostly autosomal dominant but sporadic cases without family history are also reported, resulting from a de novo mutation/deletion/duplication. Intra-familial clinical variability is the rule, with incomplete penetrance. X-linked or autosomal recessive inheritance has also been described. To date, seven subgroups of split hand foot malformation have been identified and seven loci are currently known. Anatomical records have enhanced our knowledge of this group of disorders of the hands and feet and allowed us to improve surgical procedures and long-term outcome.

Epidermal Nevi and Related Syndromes -- Part 1: Keratinocytic Nevi. / Nevus epidérmicos y síndromes relacionados. Parte 1: nevus queratinocíticos.

Epidermal nevi are hamartomatous lesions derived from the epidermis and/or adnexal structures of the skin; they have traditionally been classified according to their morphology. New variants have been described in recent years and advances in genetics have contributed to better characterization of these lesions and an improved understanding of their relationship with certain extracutaneous manifestations. In the first part of this review article, we will look at nevi derived specifically from the epidermis and associated syndromes.

Postaxial limb hypoplasia (PALH): the classification, clinical features, and related developmental biology.

Postaxial limb hypoplasia (PALH) is a group of nonhereditary diseases with congenital lower limb deficiency affecting the fibular ray, including fibular hemimelia, proximal femoral focal deficiency, and tarsal coalition. The etiology and the developmental biology of the anomaly are still not fully understood. Here, we review the previous classification systems, present the clinical features, and discuss the developmental biology of PALH.

Congenital limb deficiencies in Alberta-a review of 33 years (1980-2012) from the Alberta Congenital Anomalies Surveillance System (ACASS).

The birth prevalence of limb deficiencies in Alberta has been fluctuating. The objectives were to examine patterns and temporal trends of congenital limb deficiencies in Alberta and compare rates with those of other jurisdictions. The Alberta Congenital Anomalies Surveillance System data on live births, stillbirths, and terminations of pregnancy (<20 weeks gestation) occurring between 1980 through 2012 with the ICD-10 Royal College of Paediatrics and Child Health Adaptations codes Q71-Q73 (limb reduction defects), Q79.80 (congenital constriction bands), and Q87.24 (sirenomelia syndrome) were reviewed. Cases were classified as having amelia, transverse, longitudinal (preaxial, postaxial, central, or mixed), intercalary, split hand/split foot, complex, or other type of limb deficiency. Phenotypes were classified as associated, which included cases with a known etiology and cases with at least one other type of anomaly, or isolated. From 1980 through 2012, 795 cases were ascertained from 1,411,652 live births and stillbirths, giving a prevalence of 5.6/10,000 total births. Mixed longitudinal deficiencies were the most common (22.4%). The upper limbs (63.9%) were affected more often than the lower limbs (25.3%). Isolated limb deficiencies occurred in 43.6% of cases, 28.4% had Mendelian or other known conditions, 21.9% had multiple congenital anomalies, 5.4% had chromosome abnormalities and 0.6% were due to teratogens. The associated group, showed a significant increasing trend (P = 0.023). While the overall limb deficiency rates show very little differences across diverse populations and differing time periods, comparisons of subgroups should be made with caution, because variations in terminology and classification contribute to reported differences.

Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations.

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis-ptosis-intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello-Carey syndrome as well as the patient reported to have a "new" syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello-Carey syndrome, and suggest the single designation "Kaufman oculocerebrofacial syndrome".

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.

Anatomic and etiological classification of congenital limb deficiencies.

Limb deficiencies, the congenital absence or hypoplasia of a long bone and/or digits, vary greatly in their anatomy and etiology. Previous attempts to classify the range of possible phenotypes have not included all types of deficiencies. We present a new classification system, which includes all potential phenotypes. Infants with limb deficiencies were identified in the hospital-based Active Malformations Surveillance Program at Brigham and Women's Hospital in Boston, MA from the years 1972 to 1974 and 1979 to 2000. Affected infants were classified based on the anatomy and apparent cause of their deficiencies. The prevalence rate of all types of limb deficiency was 0.79/1,000. Upper limb deficiencies were significantly more common than lower limb deficiencies. There was no significant difference in frequencies between deficiencies on the left and right sides of the body. Longitudinal defects were more common than terminal transverse defects; intercalary defects were uncommon. Longitudinal defects were most likely to occur on the preaxial side of the limb. Almost half of affected infants had affected digits, with normal long bones. The most common apparent cause of limb deficiencies was vascular disruption defects (0.22/1,000), such as amniotic band-related limb deficiency. This new classification system includes deficiency of each long bone, as well as absence of any finger or toe. This system will make it possible to establish the prevalence of each specific phenotype. The large number of distinct apparent causes illustrates the marked etiologic heterogeneity of limb deficiencies.

Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.

Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of approximately 1.3 Mb was performed. A microduplication of approximately 5.5 kb in a noncoding sequence approximately 110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. The duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb.

Elements of morphology: standard terminology for the hands and feet.

An international group of clinicians working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we introduce the anatomy of the hands and feet and define and illustrate the terms that describe the major characteristics of the hands and feet.

[Clinical classification of congenital limb abnormalities]. / Veleszületett végtagfejlodési rendellenességek klinikai osztályozása.

Limb developmental defects are well-known, conspicuous abnormalities. Until this day, the background has still not been completely revealed, however, the development of scientific methods provides more and more opportunities which may help to understand developmental processes and defects of this compound system. Considering these aspects, following data collection from patients with limb developmental defects, we began a study with the purpose of finding/establishing a classification system that is suitable for morphological and clinical distinctions, besides considering developmental aspects, and may help to indicate adequate genetic examinations. To classify 195 patients included in our database, we chose a worldwide accepted table from Swanson. Based upon our observations we proposed some alterations, which finally lead to a table, suitable for patient classification based upon morphology and clinical features. Furthermore it allows comparisons concerning developmental aspects, gives reasonable background for genetic studies and is suitable for everyday clinical usage.

Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects.

The congenital malformation Split Hand-Foot Malformation (SHFM, or ectrodactyly) is characterized by a medial cleft of hands and feet, and missing central fingers. Five genetically distinct forms are known in humans; the most common (type-I) is linked to deletions of DSS1 and the distalless-related homeogenes DLX5 and DLX6. As Dlx5;Dlx6 double-knockout mice show a SHFM-like phenotype, the human orthologs are believed to be the disease genes. SHFM-IV and Ectrodactyly-Ectodermal dysplasia-Cleft lip (EEC) are caused by mutations in p63, an ectoderm-specific p53-related transcription factor. The similarity in the limb phenotype of different forms of SHFM may underlie the existence of a regulatory cascade involving the disease genes. Here, we show that p63 and Dlx proteins colocalize in the nuclei of the apical ectodermal ridge (AER). In homozygous p63- (null) and p63EEC (R279H) mutant limbs, the AER fails to stratify and the expression of four Dlx genes is strongly reduced; interestingly, the p63+/EEC and p63+/- hindlimbs, which develop normally and have a normally stratified AER, show reduced Dlx gene expression. The p63+/EEC mutation combined with an incomplete loss of Dlx5 and Dlx6 alleles leads to severe limb phenotypes, which are not observed in mice with either mutation alone. In vitro, DeltaNp63alpha induces transcription from the Dlx5 and Dlx6 promoters, an activity abolished by EEC and SHFM-IV mutations, but not by Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) mutations. ChIP analysis shows that p63 is directly associated with the Dlx5 and Dlx6 promoters. Thus, our data strongly implicate p63 and the Dlx5-Dlx6 locus in a pathway relevant in the aetio-pathogenesis of SHFM.

Abnormal urethra formation in mouse models of split-hand/split-foot malformation type 1 and type 4.

Urogenital birth defects are one of the common phenotypes observed in hereditary human disorders. In particular, limb malformations are often associated with urogenital developmental abnormalities, as the case for Hand-foot-genital syndrome displaying similar hypoplasia/agenesis of limbs and external genitalia. Split-hand/split-foot malformation (SHFM) is a syndromic limb disorder affecting the central rays of the autopod with median clefts of the hands and feet, missing central fingers and often fusion of the remaining ones. SHFM type 1 (SHFM1) is linked to genomic deletions or rearrangements, which includes the distal-less-related homeogenes DLX5 and DLX6 as well as DSS1. SHFM type 4 (SHFM4) is associated with mutations in p63, which encodes a p53-related transcription factor. To understand that SHFM is associated with urogenital birth defects, we performed gene expression analysis and gene knockout mouse model analyses. We show here that Dlx5, Dlx6, p63 and Bmp7, one of the p63 downstream candidate genes, are all expressed in the developing urethral plate (UP) and that targeted inactivation of these genes in the mouse results in UP defects leading to abnormal urethra formation. These results suggested that different set of transcription factors and growth factor genes play similar developmental functions during embryonic urethra formation. Human SHFM syndromes display multiple phenotypes with variations in addition to split hand foot limb phenotype. These results suggest that different genes associated with human SHFM could also be involved in the aetiogenesis of hypospadias pointing toward a common molecular origin of these congenital malformations.

Prenatal ultrasonographical features of limb body wall complex: a review of etiopathogenesis and a new classification.

Limb body wall complex is a spectrum of multiple severe anomalies. The etiopathogenesis and clinical classification are still under discussion. In our article, while reviewing previous etiopathogenetical hypothesis, we propose a new clinical classification regarding embryological theories and pheneotypical features. According to the Van Allen diagnostic criteria, the findings of 6 affected fetuses are presented. Prenatal diagnosis was performed in 5 of 6 cases. Craniofacial malformations were present in only 1 case. Thoracic defect and abdominoschisis (either infraumbilical or supraumbilical) associated with visceral eventration, placental-umbilical cord anomalies, and limb defects were detected in the other 5 cases. Aberrant development of each of the 4 embryonic folds (cephalic, 2 lateral abdominal, and caudal) associated with faulty umbilical ring development and placental formation were considered responsible for development of various malformations. In previous clinical classifications, existence or absence of the craniofacial malformation was utilized as an unique discriminating criterion while multiple anomalies exist. In this report, we propose a new clinical classification concerning almost all anomalies caused by defective placental attachment and maldevelopment of the 4 folds.

[Anatomical basis of classifications of congenital limbs deficiencies]. / Anatomiczne podstawy klasyfikacji wrodzonych ubytków konczyn.

The wide range of the congenital skeletal limb deficiencies caused difficulties with their classification. We present the most fundamentally and the most common classifications of the congenital skeletal defects.

A morpho-etiological description of congenital limb anomalies.

BACKGROUND: Limb anomalies rank behind congenital heart disease as the most common birth defects observed in infants. More than 50 classifications for limb anomalies based on morphology and osseous anatomy have been drafted over the past 150 years. The present work aims to provide a concise summary of the most common congenital limb anomalies on a morpho-etiological basis. PATIENTS AND METHODS: In a retrospective study, 70 newborns with anomalies of the upper and/or lower limbs were ascertained through clinical examination, chromosomal analysis, skeletal surveys and other relevant investigations. RESULTS: Fetal causes of limb anomalies represented 55.8% of the cases in the form of 9 cases (12.9%) with chromosomal aberrations (trisomy 13, 18 and 21, duplication 13q and deletion 22q) and 30 cases (42.9%) with single gene disorders. An environmental etiology for limb anomalies was diagnosed in 11 cases (15.7%) as amniotic band disruption, monozygotic twin with abnormal circulation, vascular disruption (Poland sequence, sirenomelia and general vascular disruption) and an infant with a diabetic mother. Twenty cases (28.5%) had limb anomalies as part of sporadic syndromes of unknown etiology. CONCLUSIONS: The morpho-etiological work-up of limb anomalies adopted in the present study is valuable for detecting the cause of the anomaly and is crucial for its prevention. Prevention can be achieved by proper genetic counseling, which includes recurrence risk estimation and prenatal diagnosis.