A novel homozygous RIPK4 variant in a family with severe Bartsocas-Papas syndrome.

Bartsocas-Papas syndrome (BPS) is a rare autosomal recessive disorder characterized by popliteal pterygia, syndactyly, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and genital malformations. Most of the BPS cases reported to date are fatal either in the prenatal or neonatal period. Causative genetic defects of BPS were mapped on the RIPK4 gene encoding receptor-interacting serine/threonine kinase 4, which is critical for epidermal differentiation and development. RIPK4 variants are associated with a wide range of clinical features ranging from milder ectodermal dysplasia to severe BPS. Here, we evaluated a consanguineous Turkish family, who had two pregnancies with severe multiple malformations compatible with BPS phenotype. In order to identify the underlying genetic defect, direct sequencing of the coding region and exon-intron boundaries of RIPK4 was carried out. A homozygous transversion (c.481G>C) that leads to the substitution of a conserved aspartic acid to histidine (p.Asp161His) in the kinase domain of the protein was detected. Pathogenicity predictions, molecular modeling, and cell-based functional assays showed that Asp161 residue is required for the kinase activity of the protein, which indicates that the identified variant is responsible for the severe BPS phenotype in the family.

Relationship between lower-extremity defects and body mass among polish children: a cross-sectional study.

BACKGROUND: Lower extremity defects in healthy children raises interest of researchers as confirmed by numerous published original and review articles. The relationship between lower extremity postural defects and body mass are unclear as published data are inconclusive. The aim of the present cross-sectional study was to analyse the prevalence of lower extremity defects in a large group of 8- to 12-year-old children; and further to assess the probability of defects associated with values of body mass variables. METHODS: The study included prospective anthropometric measurements data of 6992 children (3476 boys and 3516 girls) from Gdansk (Northern Poland). Standard screening test used in Poland for assessment of lower limb defects were used (intermalleolar or intercondylar distance for knee alignment, linear vertical compass for valgus heel, computer podoscope or classical footprint and measuring the Sztriter-Godunow index for flatfeet). Body mass was assessed with local centile charts and IOTF cutoffs. Prevalence of postural defects was compared with an aid of Pearson's chi-squared test and Fisher's exact test. Probability of lower extremities postural defect was estimated on the basis of logistic regression analysis, and expressed as an odds ratio (OR) and its 95.0% CI. RESULTS: The study demonstrated that cumulative prevalence of lower extremity defects (31.5%) was lower than reported in most published studies, most common defects were valgus heel (21.8%) and valgus knee (14.5%). Boys were significantly more frequently diagnosed with lower limb defects overall (p < 0.001), as well as with varus knee, valgus heel, flatfoot of any degree. Limb defects were found in 90,2% of obese children, 25,7% of normal weight and 15,1% of underweight children. CONCLUSIONS: Prevalence of some lower extremities defects seems to be sex specific. Prevalence varied across body weight categories and was rising with the increase of BMI. Increased body mass is correlated with a higher risk of developing lower extremity postural defects in children.

Congenital limb deficiency in Japan: a cross-sectional nationwide survey on its epidemiology.

BACKGROUND: Congenital limb deficiency is a rare and intractable disease, which impairs both function and appearance of the limbs. To establish adequate medical care, it is necessary to reveal the actual conditions and problems associated with this disease. However, there have been no extensive epidemiological surveys in Japan addressing this disease. This is the first nationwide epidemiological survey of congenital limb deficiency in this country. METHODS: With the cooperation of epidemiology experts, we performed a two-stage nationwide survey to estimate the number of patients with congenital limb deficiency and reveal basic patient features. We targeted orthopaedic surgery, paediatric, and plastic surgery departments. Hospitals were categorized according to the institution type and the number of hospital beds; hospitals were randomly selected from these categories. We selected 2283 departments from a total 7825 departments throughout Japan. In this study, we defined congenital limb deficiency as partial or total absence of the limbs, proximal to the proximal interphalangeal joint of the fingers/lesser toes or interphalangeal joint of the thumb/great toe. We distributed the first survey querying the number of initial patient visits from January 2014 to December 2015. Targets of the second survey were departments that reported one or more initial patient visits in the first survey. RESULTS: In the first survey, 1767 departments responded (response rate: 77.4%). Among them, 161 departments reported one or more initial patient visits. We conducted the second survey among these 161 departments, of which 96 departments responded (response rate: 59.6%). The estimated number of initial visits by patients with congenital limb deficiency was 417 (95% confidence interval: 339-495) per year in 2014 and 2015. The estimated prevalence of congenital limb deficiency in Japan was 4.15 (95% confidence interval: 3.37-4.93) per 10,000 live births. The sex ratio was 1.40. Upper limbs were more affected than lower limbs. CONCLUSIONS: We revealed the estimated number of initial patient visits per year and birth prevalence of congenital limb deficiency in Japan. Our results will contribute to establishing the disease concept and grades of severity of congenital limb deficiency.

[CHARACTERISTICS AND TRENDS OF CONGENITAL AND ACQUIRED LOWER LIMB DEFICIENCY IN CHILDREN AND ADOLESCENTS AT THE SHEBA MEDICAL CENTER].

INTRODUCTION: Lower limb deficiency in childhood has an impact on acquisition of motor skills. Information regarding the characteristics of this population was examined in several countries but not in Israel. AIMS: To provide demographics, clinical and functional characteristics of children with lower limb deficiency in a pediatric rehabilitation department. METHODS: Children with lower limb deficiency participated in this study. The study variables included demographics, and clinical and functional characteristics. The statistical analysis included calculations of frequency, chi-squared tests and correlations. RESULTS: During the years 1998-2015 fifty-eight children with lower extremity deformity were treated/examined in the department (mean age: 6.46+4.70 years; girls, n=21; congenital deformity, n=23; acquired deformity, n=35). The most common congenital and acquired injury was unilateral leg deformity (31% and 35%, respectively). In congenital injury, multi-limb deformity (including an involvement in the upper limb) is more prevalent than bilateral lower limb deformity (p<0.01). In children with congenital deformity, longitudinal deformity is more prevalent than transverse deformity (p<0.03). Among children with acquired injury, in 40% the etiology was sickness-related and in the rest traumatic. Among the traumatic group, 57% of the injuries were terror-related. More than 50% percent of the children underwent a complex surgical procedure (34% and 22% among congenital and acquired injury, respectively). The ambulation level of the sample was lower than expected. CONCLUSIONS: Children who received treatment due to lower limb deformity presented high variability in their characteristics and low ambulation level. Consequently, it is important to create and manage a register for pediatric lower limb deformity.

Congenital tibial deficiency: a 37-year experience at 1 institution.

BACKGROUND: The purpose of this study is to evaluate all cases of tibial deficiency seen at a single institution from 1975 to 2012, to classify these cases by the Jones classification if possible, to evaluate for associated anomalies, and to review the surgical treatments provided to these patients. METHODS: Ninety-five patients (125 extremities) treated at our institution between 1975 and 2012 with tibial deficiency had complete records allowing for classification and review of full treatment course. These patients' records and imaging were retrospectively reviewed for any associated anomalies, surgical treatment performed, and limb deformity characterized by the Jones classification where possible. RESULTS: Seventy-three of 125 limbs (58%) were classified as Jones type 1A, 6 (5%) as type 1B, 18 (14%) as type 2, and 12 (10%) as type 4. Two limbs initially classified radiographically as type 3 deformities subsequently developed a proximal tibia epiphyses and thus did not represent true type 3 deformities. Fourteen limbs (11%) were characterized by global tibial deficiency but with proximal and distal epiphyses and could not be classified according to the Jones classification. Seventy-five of the 95 patients (79%) had associated anomalies. Other lower extremity anomalies were most frequent; however, upper extremity, spine, and visceral anomalies were also noted. CONCLUSIONS: True type 3 deformity as described by Jones was not seen in our patient population; all patients developed a proximal epiphysis. Therefore, this group may be better served by limb salvage than amputation. Fourteen (11%) limbs, characterized by global tibia shortening relative to the fibula of variable degree, could not be classified according to the Jones classification. We propose adding this group as a new group within the Jones classification, which we call type 5. Finally, in this patient population, the Brown procedure for type 1 tibial deficiency universally failed, confirming results of prior studies. LEVEL OF EVIDENCE: This is a level IV study, a retrospective review of 95 patients with tibial deficiency from a single institution.

Early prenatal exposure to air pollution and its associations with birth defects in a state-wide birth cohort from North Carolina.

BACKGROUND: Few studies have examined the potential relationship between air pollution and birth defects. The objective of this study was to investigate whether maternal exposure to particulate matter (PM2.5 ) and ozone (O3 ) during pregnancy is associated with birth defects among women living throughout North Carolina. METHODS: Information on maternal and infant characteristics was obtained from North Carolina birth certificates and health service data (2003-2005) and linked with information on birth defects from the North Carolina Birth Defects Monitoring Program. The 24-hr PM2.5 and O3 concentrations were estimated using a hierarchical Bayesian model of air pollution generated by combining modeled air pollution predictions from the U.S. Environmental Protection Agency's Community Multi-Scale Air Quality model with air monitor data from the Environmental Protection Agency's Air Quality System. Maternal residence was geocoded and assigned pollutant concentrations averaged over weeks 3 to 8 of gestation. Binomial regression was performed and adjusted for potential confounders. RESULTS: No association was observed between either PM2.5 or O3 concentrations and most birth defects. Positive effect estimates were observed between air pollution and microtia/anotia and lower limb deficiency defects, but the 95% confidence intervals were wide and included the null. CONCLUSION: Overall, this study suggested a possible relationship between air pollution concentration during early pregnancy and certain birth defects (e.g., microtia/anotia, lower limb deficiency defects), although this study did not have the power to detect such an association. The risk for most birth defects does not appear to be affected by ambient air pollution.

Prevalence and trends of selected congenital malformations in New York State, 1983 to 2007.

BACKGROUND: Major birth defects result in high infant mortality and morbidity. It is important to evaluate the burden of birth defects and trends for future intervention and public health improvement. Using the New York State (NYS) Congenital Malformations Registry data, we examined the prevalence and trends of birth defects among children in NYS during 25 years of surveillance. METHODS: Children who had any of the 21 selected birth defects and were born to NYS residents between 1983 and 2007 were selected. The prevalence of each defect was characterized by demographic and birth factors, and the prevalence ratio was calculated. Live births of NYS residents for the same birth year period were used as the denominators for calculating the prevalence. The prevalence trends of birth defects were analyzed by maternal age and race/ethnicity. RESULTS: Compared with non-Hispanic whites, we detected 33%, 21%, and 37% higher prevalence of encephalocele, lower limb deficiencies and omphalocele among non-Hispanic blacks, respectively, and 22% higher prevalence of gastroschisis among Hispanics. Increasing trends of gastroschisis and Down syndrome among non-Hispanic blacks and decreasing trends of spina bifida and limb deficiencies were observed in NYS. CONCLUSION: The findings from this study suggest the existence of racial disparities among children with selected birth defects in NYS. The increasing trends of gastroschisis and Down syndrome observed in NYS are consistent with nationwide trends.

Upper extremity anomalies in children with femoral and fibular deficiency.

Defects occurring in the femoral-fibular-ulnar developmental field are believed to cause the cluster of anomalies seen with femoral, fibular and ulnar limb deficiencies. Upper limb function must be considered in the management of lower limb deficiencies. The purpose of this study is to determine the frequency and type of upper extremity anomalies found in children with femoral and/or fibular deficiency. A retrospective review of 327 consecutive patients with the diagnosis of femoral and/or fibular deficiency was performed using existing records and radiographs. Characteristics of those with and without upper extremity anomalies were compared. Upper extremity anomalies were identified in 56 patients. They were more common among those with bilateral, compared with unilateral, lower extremity deficiencies (P < 0.0001). Seventy-five upper limbs were involved with 50 ulnar deficiencies, nine congenital transhumeral deficiencies, four congenital shoulder disarticulations, seven cleft hands, two radial head dislocations and one each - radial deficiency, syndactyly and capitate-lunate coalition. Two patients with bilateral upper extremity anomalies had ulnar deficiency on one side and a transverse deficiency on the other. Upper extremity anomalies are found in 17% of children with femoral and/or fibular deficiency, especially with bilateral lower extremity involvement. Ulnar deficiency is the most common type but one-third had other anomalies. The frequent finding of congenital transverse upper extremity deficiencies suggests there may be common embryology.

Prevalence of Lower Limb Defects in Children in Chosen Kindergartens of the Lódz Agglomeration.

BACKGROUND: Posture disorders not treated in early childhood may lead to serious diseases and dysfunctions later. The aim of the study was to assess the incidence of lower limb defects in pre-school children. MATERIAL AND METHODS: The study covered 513 children (252 girls and 261 boys) aged 4-6, in chosen kinder-gartens of the Lódz agglomeration . The child's body posture was assessed using a visual method based on the Kasperczyk scoring scale in own modification. RESULTS: Foot defects occurred in the examined group with a frequency of 85.58% (439/513): in 4-year-olds: 82.59%, in 5- and 6-year-olds: 87.5%. Foot defects were more common in girls in the entire study group (86.9 vs. 84.29%), in 4-year-olds (87.88 vs. 77.45%) and 6-year-olds (88.89 vs. 86.25%), and in boys in the 5-year-olds group (91.14 vs. 83.95%). Defects of the knee joints, including varus and valgus knee, occurred in the study group with a frequency of 52.83% (271/513): in 4-year-olds: 56.72%, in 5-year-olds: 45.63% and in 6-year-olds: 55.26%. Defects were more frequent in girls in the entire study group (54.37 vs. 51.34) and in 4-year-olds (58.59 vs. 54.90%), and in boys in the 5-year-old group (50.63 vs. 40.74%). In the 6-year-olds group, the defects were statistically significantly more common in girls than boys (63.89 vs. 47.5%, p = 0.0442). CONCLUSION: A high percentage of lower limb defects rate at more than half of the examined pre-school children population is disturbing and requires effective systemic action.

Abnormal findings on knee magnetic resonance imaging in asymptomatic NBA players.

The purpose of this study was to evaluate the knees of asymptomatic National Basketball Association (NBA) players via magnetic resonance imaging (MRI) and confirm or dispute findings reported in the previous literature. It is thought that a variety of significant abnormalities affecting the knee exist in asymptomatic patients and that these findings can be accurately identified on MRI. Two months prior to the 2005 season, bilateral knee MRI examinations of 14 asymptomatic NBA players (28 knees) were evaluated for abnormalities of the articular cartilage, menisci, and patellar and quadriceps tendons. The presence of joint effusion, subchondral edema, and cystic lesions and the integrity of the collateral and cruciate ligaments were also assessed.

Clinical and epidemiological features of Heart-Hand Syndrome: a hospital-based study in China.

Heart-hand syndrome (HHS) is a clinically and genetically heterogeneous disorder characterized by the co-occurrence of a congenital cardiac disease and an upper limb malformation. This study revealed the clinical and epidemiological features of HHS in China. The study was based on patients with congenital upper limb malformation treated in Beijing Ji Shui Tan hospital from October 1st, 2013 to October 1st, 2016. We reviewed the patients' medical records and identified patients with abnormal ultrasonic cardiogram and/or electrocardiogram (ECG). A total of 1462 patients (910 male and 552 female) were identified to be treated for congenital upper limb malformation. Among them, 172 (11.8%) had abnormal ultrasonic cardiogram and/or ECG. Abnormal heart structure were discovered in 121 patients and 51 patients had abnormal ECG. The most common type of abnormal heart structure was tricuspid regurgitation (53/121, 43.8%), while the most common abnormal ECG was wave patterns (22/51, 43.1%). This hospital-based study suggests that the rate of congenital heart disease is high in patients treated for congenital upper extremity malformation in China. Surgeons and anesthetists should be aware of the comorbidity and preoperational examination of congenital heart diseases is highly needed to avoid complications during operation.

High risk for major nonlimb anomalies associated with lower-limb deficiency: a population-based study.

BACKGROUND: The aims of this study were to determine the prevalence of congenital lower-limb reduction defects and associated mortality, to evaluate lower-limb deficiencies by type of reduction, and to identify patterns of associated anomalies. METHODS: We conducted a population-based study with use of data from the Finnish Register of Congenital Malformations and Care Register for Health Care. All cases of lower-limb deficiency among live births, stillbirths, spontaneous abortions, and terminations of pregnancy due to fetal anomalies from 1993 to 2008 were included. We analyzed medical records and classified lower-limb reduction defects. Associated major anomalies were recorded, and perinatal mortality and infant mortality were calculated. RESULTS: Two hundred and sixty-six cases with lower-limb deficiency were identified, with a total prevalence of 2.8 per 10,000 births, a birth prevalence of 2.2 per 10,000 births, and a live-birth prevalence of 2.1 per 10,000 live births. Terminal transverse limb reductions accounted for 44.7% of the cases; longitudinal reductions, 22.9%; intercalary reductions, 7.9%; multiple reductions, 8.3%; and split-foot malformations, 4.5%. In addition to lower-limb deficiency, 47.7% of the cases had other major anomalies; anomalies of internal organs were noted in 26.3% of the cases, anomalies of the axial skeleton in 13.5% of cases, and central nervous system anomalies in 12.8%. Upper-limb reductions were observed in 32.0% of the cases. The relative risk (RR) for associated major anomalies was 12.54 (95% confidence interval [CI], 11.06 to 14.23) compared with the general figures for major congenital anomalies in Finland. The RR for associated anomalies was higher (1.75; 95% CI, 1.20 to 2.53) for longitudinal preaxial lower-limb deficiencies than for the other types of lower-limb reductions. Perinatal mortality was seventy-eight per 1000 births. All infant deaths were associated with chromosomal abnormalities, other known syndromes, or additional congenital malformations. CONCLUSIONS: Nearly half of the cases with lower-limb deficiencies were found to have other major anomalies. In cases of preaxial lower-limb deficiencies, the risk for associated major anomalies was highest.

Holt Oram syndrome: a registry-based study in Europe.

BACKGROUND: Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterised by upper limb anomalies and congenital heart defects. We present epidemiological and clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. METHODS: The study was based on data collected during 1990-2011 by 34 registries. The registries are population-based and use multiple sources of information to collect data on all types of birth using standardized definitions, methodology and coding. Diagnostic criteria for inclusion in the study were the presence of radial ray abnormalities and congenital heart disease (CHD), or the presence of either radial ray anomaly or CHD, with family history of HOS. RESULTS: A total of 73 cases of HOS were identified, including 11 (15.1%) TOPFA and 62 (84.9%) LB. Out of 73 HOS cases, 30.8% (20/65) were suspected prenatally, 55.4% (36/65) at birth, 10.7% (7/65) in the first week of life, and 3.1% (2/65) in the first year of life. The prenatal detection rate was 39.2% (20/51), with no significant change over the study period. In 55% (11/20) of prenatally detected cases, parents decided to terminate pregnancy. Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2% (30/61), ulnar aplasia/hypoplasia in 24.6% (15/61) and humerus hypoplasia/phocomelia in 42.6% (26/61) of patients. Congenital heart defects (CHD) were recorded in 78.7% (48/61) of patients. Isolated septal defects were present in 54.2 (26/48), while 25% (12/48) of patients had complex/severe CHD. The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births. CONCLUSIONS: HOS is a rare genetic condition showing regional variation in its prevalence. It is often missed prenatally, in spite of the existence of major structural anomalies. When discovered, parents in 45% (9/20) of cases opt for the continuation of pregnancy. Although a quarter of patients have severe CHD, the overall first week survival is very good, which is important information for counselling purposes.

Causes and consequences of the deficiencies of the lower limbs in the Republic of Guinea.

PURPOSE: According to the last general census of 1996, the deficiency of lower limbs is the main cause of handicap in the Republic of Guinea. The objective of this study that took place in 2008 in Conakry is to analyze the main causes of this phenomenon, as well as to understand the reasons of their increase within the Guinean capital. METHOD: Our survey covered 244 Guineans out of which 170 men and 74 women were living in Conakry, aged between 10 and 68 years old (±12,6). RESULTS: The main causes of the deficiencies are the poliomyelitis after-effects (40%), as well as other risk factors such as the road accidents and the failure of the health system. Whatever the nature of the deficiencies, their compensation is mainly based on the technical supports such as tricycles and wheelchairs. However, they are distributed in a random way and without any medical follow-up. CONCLUSION: The orthopedic care in the Republic of Guinea is insufficient and inadequate. Hence, certain individuals who need it the most do not receive it. This type of care is not always helpful and sometimes harmful to the health of the disabled persons.

Spinal neural tube defects in Lagos University Teaching Hospital, Nigeria.

BACKGROUND: The incidence of neural tube defects is known to vary among regions. Very little has been reported about the incidence in Sub-Saharan Africa except for the general impression that the prevalent rates are low. OBJECTIVE: To determine the profile of patients presenting with neural tube defects in Lagos, Nigeria METHODS: We studied all patients with congenital midline back swellings presenting to one of two neurosurgical services in the state over a 5-year period to establish the incidence of spina bifida and develop demographic data. Data collected included the age at presentation, maternal age, education and parity, presence of co-existing anomalies and the social status of the parents. RESULTS: One hundred and eight patients with congenital midline swellings of the back were studied. Meningomyelocele accounted for 96% of the cases seen. Half the patients presented within the first two weeks of life and although fifty percent of mothers had ultrasound scans done during pregnancy none of the patients were diagnosed prenatally. Seventy-three percent of mothers of affected children were from a low socio-economic class. The commonest co-existing congenital anomaly was lower limb deformity (Talipes equino-varus). CONCLUSION: Spina bifida is the commonest indication for neurosurgical clinic referral with the exception of trauma in our environment. The prevalence is higher among women in the lower socio-economic groups. Improved perinatal care is required to ensure that children with such birth defects get prompt medical attention and thereby prevent worsening of an already complex problem.

HLXB9 homeobox gene and caudal regression syndrome.

BACKGROUND: Caudal regression syndrome (CRS) is a congenital heterogeneous constellation of caudal anomalies that include varying degrees of agenesis of the spinal column, anorectal malformations (ARMs), genitourinary anomalies, and pulmonary hypoplasia. The combination of a particular form of hemisacrum, ARM, and presacral mass (teratoma, anterior meningocele, rectal duplication, or a combination thereof) constitutes Currarino syndrome (CS). Previous reports have shown HLXB9 to be a major causative gene for CS. The aim of our study was to reevaluate the involvement of the HLXB9 gene in a larger group of CRS cases. METHODS: SSCP analysis was performed on a series of 48 CRS cases without CS. A case-control approach was used to test whether an alteration of the length of the GCC triplets in exon 1 of the HLXB9 gene could contribute to CRS risk. RESULTS: No pathological variants of the HLXB9 gene were identified by mutational analysis. We also found no evidence that the length of the GCC triplets had any effect on the CRS risk, even when the allelic frequencies were stratified according to the presence or absence of ARMs and the type of sacral agenesis. CONCLUSIONS: We confirmed that the HLXB9 gene is not involved in the pathogenesis of CRS, and to date is known as a causative gene only for CS.