Cancer risk in individuals with polydactyly: a Swedish population-based cohort study.

BACKGROUND: Polydactyly is a feature of several cancer predisposition syndromes (CPS), however, cancer risk in individuals with polydactyly is largely unknown. METHODS: We performed a matched cohort study using data from Swedish national registers. We included 6694 individuals with polydactyly, born in Sweden between 1970-2017. Polydactyly was categorised as thumb polydactyly, finger polydactyly, polydactyly+ (additional birth defects and/or intellectual disability) or isolated polydactyly. Each exposed individual was matched to 50 comparisons by sex, birth year and birth county. Associations were estimated through Cox proportional hazard models. FINDINGS: An increased childhood cancer risk was found in males (HR 4.24, 95% CI 2.03-8.84) and females (HR 3.32, 95% CI 1.44-7.63) with polydactyly+. Isolated polydactyly was associated with cancer in childhood (HR 1.87, 95% CI 1.05-3.33) and young adulthood (HR 2.30, 95% CI 1.17-4.50) in males but not in females. The increased cancer risk remained after exclusion of two known CPS: Down syndrome and neurofibromatosis. The highest site-specific cancer risk was observed for kidney cancer and leukaemia. CONCLUSIONS: An increased cancer risk was found in individuals with polydactyly, especially in males and in individuals with polydactyly+. We encourage future research about polydactyly and cancer associations and emphasise the importance of clinical phenotyping.

Measuring the aesthetic and functional outcome of pollicization.

We retrospectively investigated the importance of aesthetics after pollicization in 12 pollicized thumbs in nine patients with current objective and subjective measurements. Subjective improvements in appearance and function correlated even though improvement of function was of greater importance.

Detection of germline mosaicism in fathers of children with intellectual disability syndromes caused by de novo variants.

BACKGROUND: De novo variants are a common cause to rare intellectual disability syndromes, associated with low recurrence risk. However, when such variants occur pre-zygotically in parental germ cells, the recurrence risk might be higher. Still, the recurrence risk estimates are mainly based on empirical data and the prevalence of germline mosaicism is often unknown. METHODS: To establish the prevalence of mosaicism in parents of children with intellectual disability syndromes caused by de novo variants, we performed droplet digital PCR on DNA extracted from blood (43 trios), and sperm (31 fathers). RESULTS: We detected low-level mosaicism in sperm-derived DNA but not in blood in the father of a child with Kleefstra syndrome caused by an EHMT1 variant. Additionally, we found a higher level of paternal mosaicism in sperm compared to blood in the father of a child with Gillespie syndrome caused by an ITPR1 variant. CONCLUSION: By employing droplet digital PCR, we detected paternal germline mosaicism in two intellectual disability syndromes. In both cases, the mosaicism level was higher in sperm than blood, indicating that analysis of blood alone may underestimate germline mosaicism. Therefore, sperm analysis can be clinically useful to establish the recurrence risk for parents and improve genetic counselling.

[The pain killer bag - optimized pain treatment and reduced prescription of opioids after outpatient hand surgery]. / Smärtpåse minskade smärta och opioidförskrivning vid dagkirurgi.

Patients normally use opioids for less than 3 days after soft tissue and simple bone surgery in the upper extremity [2], but packages of prescribed medications include many pills beyond this need. To address this, we designed a bag of painkillers to optimize pain treatment, primarily for those with long lasting brachial plexus block that may have severe pain debut at home [1]. The bag includes seven oxycodone tablets of 5 mg, and 1 day's worth of ibuprofen and paracetamol in case patients did not buy these preoperatively as instructed. For those with long-lasting ropivacaine brachial plexus block, smart bag treatment was timed to begin 7 hours after ropivacaine initiation. Based on interviews of the first 103 patients, 78% were satisfied. Surgeons and nurses also appreciated the reduced administrative tasks and faster patient discharge.

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth.

PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles.

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.

[Hand transplantation in Sweden ­ preparations under way]. / Handtransplantation snart verklighet i Sverige.

English summary: Hand transplantation in Sweden - preparations under way Some patients with a uni- or bilateral hand- or forearm amputation cannot use a hand prosthesis, although high-tech prostheses have been developed. A hand transplantation, particularly for those with bilateral amputations, may be an alternative solution. In a hand-transplanted patient, grip function, strength, sensibility and subsequent improved quality of life can be restored. Risks related to immunosuppression must be balanced by expected benefits, and thorough selection of patients has to be performed from both medical and psychological point of view. Therefore, a national network has been established in Sweden to achieve coordination with the needed competence.

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.

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.

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.

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.

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.

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.

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.