Tobias Laurell

Epidemiology of Congenital Upper Limb Anomalies in 562 Children Born in 1997 to 2007: A Total Population Study from Stockholm, Sweden

PURPOSE There are few true epidemiological studies of congenital anomalies of the upper limb (CULA) on total populations in the literature, and most incidence studies are hospital based. The purposes of this study were to describe the epidemiology and classify all CULA in a region of Sweden during an 11-year period. METHODS Between 1997 and 2007, there were 261,914 live births in the Stockholm region. A total of 562 children born during this period were found to have CULA. From medical records and available radiographs, all cases were analyzed regarding the type of congenital anomaly, gender, laterality, occurrence among relatives, associated non-hand anomalies, and syndromes. All 585 main anomalies were classified according to the International Federation of Societies for Surgery of the Hand classification. Individuals with right- and left-side main anomalies belonging to different categories were counted as having 2 anomalies. RESULTS The recorded incidence of CULA was 21.5 per 10,000 live births. Of the 562 children, 304 were boys. The anomalies affected the right side only in 169 children, the left side only in 186, and both sides in 207. Non-hand anomalies were recorded in 129 children, most commonly in the lower limbs. In 99 children, there was a known occurrence among relatives. Failure of differentiation was the most common category (276 of 585) followed by duplication (155 of 585), failure of formation (103 of 585), undergrowth (18 of 585), generalized abnormalities and syndromes (14 of 585), overgrowth (10 of 585), and constriction ring syndrome (9 of 585). CONCLUSIONS The incidence of CULA in our region was similar to the only previously comparable total population study from Western Australia. The minor differences in incidences between the categories according to the International Federation of Surgical Societies of the Hand may be due to variations in classification strategy. The results of the present study can be used as a reference of CULA in a total population.

Different mutations in PDE4D associated with developmental disorders with mirror phenotypes

Background Point mutations in PDE4D have been recently linked to acrodysostosis, an autosomal dominant disorder with skeletal dysplasia, severe brachydactyly, midfacial hypoplasia and intellectual disability. The purpose of the present study was to investigate clinical and cellular implications of different types of mutations in the PDE4D gene. Methods We studied five acrodysostosis patients and three patients with gene dose imbalances involving PDE4D clinically and by whole exome sequencing, Sanger sequencing and array comparative hybridisation. To evaluate the functional consequences of the PDE4D changes, we used overexpression of mutated human PDE4D message and morpholino-based suppression of pde4d in zebrafish. Results We identified three novel and two previously described PDE4D point mutations in the acrodysostosis patients and two deletions and one duplication involving PDE4D in three patients suffering from an intellectual disability syndrome with low body mass index, long fingers, toes and arms, prominent nose and small chin. When comparing symptoms in patients with missense mutations and gene dose imbalances involving PDE4D, a mirror phenotype was observed. By comparing overexpression of human mutated transcripts with pde4d knockdown in zebrafish embryos, we could successfully assay the pathogenicity of the mutations. Conclusions Our findings indicate that haploinsufficiency of PDE4D results in a novel intellectual disability syndrome, the 5q12.1-haploinsufficiency syndrome, with several opposing features compared with acrodysostosis that is caused by dominant negative mutations. In addition, our results expand the spectrum of PDE4D mutations underlying acrodysostosis and indicate that, in contrast to previous reports, patients with PDE4D mutations may have significant hormone resistance with consequent endocrine abnormalities.

A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/LMBR1) causes preaxial polydactyly with triphalangeal thumb

Mutations in the Sonic hedgehog limb enhancer, the zone of polarizing activity regulatory sequence (ZRS, located within the gene LMBR1), commonly called the ZRS), cause limb malformations. In humans, three classes of mutations have been proposed based on the limb phenotype; single base changes throughout the region cause preaxial polydactyly (PPD), single base changes at one specific site cause Werner mesomelic syndrome, and large duplications cause polysyndactyly. This study presents a novel mutation—a small insertion. In a Swedish family with autosomal‐dominant PPD, we found a 13 base pair insertion within the ZRS, NG_009240.1:g.106934_106935insTAAGGAAGTGATT (traditional nomenclature: ZRS603ins13). Computational transcription factor‐binding site predictions suggest that this insertion creates new binding sites and a mouse enhancer assay shows that this insertion causes ectopic gene expression. This study is the first to discover a small insertion in an enhancer that causes a human limb malformation and suggests a potential mechanism that could explain the ectopic expression caused by this mutation. Hum Mutat 33:1063–1066, 2012.

Epidemiology of Congenital Upper Limb Anomalies in Stockholm, Sweden, 1997 to 2007: Application of the Oberg, Manske, and Tonkin Classification

PURPOSE To investigate the epidemiology of congenital upper limb anomalies (CULA) based on the newly proposed Oberg, Manske, and Tonkin (OMT) classification, to compare this classification with the International Federation of Societies for Surgery of the Hand (IFSSH) classification, and to provide incidence rates of the different CULA. METHODS In this study, the same 562 individuals with a CULA who were analyzed in a previous epidemiologic study based on the IFSSH classification were reclassified according to the OMT classification. All children identified with CULA and born in Stockholm County between January 1, 1997 and December 31, 2007 were included in the study. During the period there were 261,914 live births in Stockholm County, and the population of Stockholm County was 1,949,516 inhabitants at the end of the period. From medical records and available radiographs, all cases were analyzed regarding type of CULA, sex, affected side, associated nonhand anomalies, and occurrence among relatives. Individuals with right and left side anomalies belonging to different OMT subgroups were counted as 2 anomalies; thus, the material consisted of 577 CULA in 562 children. RESULTS It was possible to organize all CULA into the OMT classification. The largest main category was malformations (429 cases), followed by deformations (124 cases), dysplasias (10 cases), and syndromes (14 cases). We present the relation between the IFSSH and OMT classifications, elucidate difficulties within the OMT classification, and propose additions to the classification. CONCLUSIONS This study confirms that the OMT classification is useful and accurate, but also points out difficulties. With further refinements, we regard the OMT classification as a needed and appropriate replacement for the IFSSH classification. TYPE OF STUDY/LEVEL OF EVIDENCE Diagnostic III.

Identification of three novel FGF16 mutations in X-linked recessive fusion of the fourth and fifth metacarpals and possible correlation with heart disease.

Nonsense mutations in FGF16 have recently been linked to X‐linked recessive hand malformations with fusion between the fourth and the fifth metacarpals and hypoplasia of the fifth digit (MF4; MIM#309630). The purpose of this study was to perform careful clinical phenotyping and to define molecular mechanisms behind X‐linked recessive MF4 in three unrelated families. We performed whole‐exome sequencing, and identified three novel mutations in FGF16. The functional impact of FGF16 loss was further studied using morpholino‐based suppression of fgf16 in zebrafish. In addition, clinical investigations revealed reduced penetrance and variable expressivity of the MF4 phenotype. Cardiac disorders, including myocardial infarction and atrial fibrillation followed the X‐linked FGF16 mutated trait in one large family. Our findings establish that a mutation in exon 1, 2 or 3 of FGF16 results in X‐linked recessive MF4 and expand the phenotypic spectrum of FGF16 mutations to include a possible correlation with heart disease.

Molecular and clinical delineation of the 17q22 microdeletion phenotype

Deletions involving 17q21–q24 have been identified previously to result in two clinically recognizable contiguous gene deletion syndromes: 17q21.31 and 17q23.1–q23.2 microdeletion syndromes. Although deletions involving 17q22 have been reported in the literature, only four of the eight patients reported were identified by array-comparative genomic hybridization (array-CGH) or flourescent in situ hybridization. Here, we describe five new patients with 1.8–2.5-Mb microdeletions involving 17q22 identified by array-CGH. We also present one patient with a large karyotypically visible deletion involving 17q22, fine-mapped to ∼8.2 Mb using array-CGH. We show that the commonly deleted region in our patients spans 0.24 Mb and two genes; NOG and C17ORF67. The function of C17ORF67 is not known, whereas Noggin, the product of NOG, is essential for correct joint development. In common with the 17q22 patients reported previously, the disease phenotype of our patients includes intellectual disability, attention deficit hyperactivity disorder, conductive hearing loss, visual impairment, low set ears, facial dysmorphology and limb anomalies. All patients displayed NOG-related bone and joint features, including symphalangism and facial dysmorphology. We conclude that these common clinical features indicate a novel clinically recognizable, 17q22 contiguous microdeletion syndrome.

Goltz syndrome in males: A clinical report of a male patient carrying a novel PORCN variant and a review of the literature

Here, we report a novel mosaic mutation in the PORCN gene in a male Goltz syndrome patient. We also compare the phenotypes of all reported males with a confirmed molecular diagnosis. This report serves to further clarify the phenotype of Goltz syndrome and suggests that expression in males varies.

Functional assessment of children and adolescents with symbrachydactyly a unilateral hand malformation

Background: We studied children and adolescents with symbrachydactyly to determine whether hand function depends on digit opposability and whether scores for function and quality-of-life measures differ from population norms. Methods: Participants were grouped on the basis of hand morphology: Group A lacked opposable digits, and Group B had ≥2 digits that were opposable. The groups were compared with each other and with norms with respect to pinch strength, the performance of bimanual activities and in-hand manipulation, and questionnaires regarding psychosocial status and the ability to perform activities of daily living (ADLs). Participants and parents also rated the appearance and function of the hand. Results: Pinch strength was higher for participants in Group B (4.1 compared with 2.4 kg; p = 0.008), but the groups did not differ with respect to the proportion of participants outside of pinch norms. Participants in Group B were more likely to actively use their affected hand to perform bimanual activities (p ⩽ 0.0009), and to use normal or supination strategies to accomplish in-hand manipulation (p = 0.031). The groups did not differ in the proportion of ADLs rated “difficult” or “impossible,” and both groups tested within normal limits for psychosocial function. Participants from both groups and their parents rated their satisfaction with hand appearance and function similarly high. Conclusions: Participants with ≥2 opposable digits incorporated their hand better in bimanual activities and used more effective strategies to accomplish in-hand manipulation than those who did not. These groups reported no difference in the ability to perform ADLs or with psychosocial function, which was within the normal range. Children and adolescents with symbrachydactyly demonstrated and reported a high level of function in all domains of validated function tests. This study provides information to help parents of children with a unilateral hand malformation understand their child’s potential function, and assist surgeons with recommending treatment. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.