Burden of rare genetic disorders in India: twenty-two years' experience of a tertiary centre.

BACKGROUND: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. RESULTS: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of ß-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), ß-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29-13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. CONCLUSION: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Role of Percutaneous Screw Fixation in Children with Delayed Presentation and Nonunion of Lateral Condyle Humerus Fractures with Elbow Stiffness.

Introduction: Delayed presentations and nonunion of lateral condyle of Humerus (LCH) fractures in children are common. It is recommended to gain elbow movements before placing single screw for late presenting LCH fractures. We examined the efficacy of a percutaneously placed screw in delayed presenting LCH fractures and LCH nonunion in children who presented with varying degree of elbow stiffness without waiting for improvement in elbow movements. Material and Methods: Sixteen children with LCH fractures presenting after six weeks of fracture, without signs of union, and with frank nonunion were treated with percutaneous placement of the cancellous screw. There was a delay of 1.5 to18 months before presenting to us. The results were assessed by Dhillon criteria. Results: All the patients at presentation had flexion deformity (avg 290) and restricted flexion ((avg 1000). Successful radiological union was achieved in fifteen patients. All the patients had full recovery of extension. Fifteen patient regained full flexion and one patient has only 100 flexion restriction (p value < 0.001). At the final follow-up, fifteen patients had excellent and one had a good overall Dhillon score. There was no clinically evident varus or valgus deformity. Conclusion: We could achieve union in a majority of the patients with delayed presentation and established nonunion of LCH fractures with simple percutaneous screw placement, thereby avoiding open surgery, big scar, bone grafting, and AVN of LCH. We did not wait for an improvement in elbow movements before screw fixation and still all our patients regained full elbow movements with improved Dhillon scores.

The GALNS p.P77R variant is a probable Gujarati-Indian founder mutation causing Mucopolysaccharidosis IVA syndrome.

BACKGROUND: Mucopolysaccharidosis IVA (Morquio syndrome A, MPS IVA) is an autosomal recessive lysosomal storage disorder caused due to biallelic variants in the N-acetylgalactoseamine-6-sulfate sulfatase (GALNS) gene. The mutation spectrum in this condition is determined amongst sub-populations belonging to the north, south and east India geography, however, sub-populations of west Indian origin, especially Gujarati-Indians, are yet to be studied. We aimed to analyse the variants present in the GLANS gene amongst the population of Gujarat by sequencing all exons and exon-intron boundaries of the GALNS gene in patients from 23 unrelated families. RESULTS: We report 11 variants that include eight missense variants: (p.L36R, p.D39G, p.P77R, p.C79R, pP125L, p.P151L, p.G255A and p.L350P), one splice site variant: (c.121-7C > G), one small insertion: (c.1241_1242insA, p.I416HfsTer2) and one small deletion: (c.839_841delACA). Of these, three missense variants (p.D39G, p.G255A and p.L350P), one splice site and the two indels mentioned above are novel. Interestingly, we observed a higher than anticipated prevalence of p.P77R variant in our cohort (n = 14/25, 56%). Haplotype analysis in cases with p.P77R variant and 63 ethnicity matched healthy population controls suggested a 4 SNP haplotype block present in cases compared to controls (likelihood ratio test p-value = 1.16 × 10-13), thereby suggesting p.P77R variant as a founder variant in the Gujarati-Indian population. Furthermore, age of mutation analysis suggested the variant to have arisen approximately 450 years ago in the population. CONCLUSION: p.P77R variant in the GLANS gene is likely to be a founder variant in MPS IVA patients of Gujarati-Indian ancestry and appeared approximately 450 years ago in the population. To our knowledge, this is the first variant to be posited as a founder variant in the GLANS gene in patients with MPS IVA syndrome.

The spectrum of tibial pseudarthrosis with constriction band syndrome in children.

Constriction band syndrome (CBS) may be rarely associated with pseudarthrosis of tibia. Published literature includes only case reports. We evaluated the outcome of children with frank pseudarthrosis of the tibia with CBS and compared our results with other reported cases. We aimed to formulate a clinical classification of tibial involvement in CBS on the basis of the treatment guidelines. Seven patients with the presence of one or more constriction bands and radiological signs of tibial pseudarthrosis were included in the study. Eight reported cases of CBS with tibial involvement with management and follow-up details were reviewed. Only two tibial pseudarthrosis united spontaneously after the release of the constriction band. Two patients underwent simultaneous correction of tibial deformity and nailing with band release, one of which needed bone grafting for the pseudarthrosis union. Three patients subsequently needed an excision of tibial pseudarthrosis with nailing to achieve tibial union, two of them had autologous bone grafting along with nailing. Additional procedures were required for the correction of foot deformity and limb length discrepancy. Our findings were similar to the reported cases. The pseudarthrosis of the tibia with CBS does not always heal following band release. Additional surgeries may be required for persistent pseudarthrosis, limb length discrepancy and residual foot deformities. A functional and radiological classification is proposed for the treatment of tibial pseudarthrosis with CBS.

Case Report: Recurrent Variant c.298 TA in CCN6 Gene Found in Progressive Pseudorheumatoid Dysplasia Patients From Patni Community of Gujarat: A Report of Three Cases.

Biallelic mutations in the CCN6 gene are known to cause a rare genetic disorder-progressive pseudorheumatoid dysplasia (PPD). PPD is characterized by distinct joint deformities of interphalangeal joints, stiffness, gait disturbance, abnormal posture, and absence of inflammation, resulting in significant morbidity. The largest case series of PPD from India suggests c.233G>A and c.1010G>A to be the most common mutations in the CCN6 gene, although the distribution of these variants among endogamous communities in India has not been carried out. We here report three cases of PPD from three independent families belonging to the Patni community of Gujarat, a community known to practice endogamy. All three cases had short stature, gait disturbance, scoliosis, and interphalangeal joint deformities. Analysis by whole-exome sequencing in the first case showed the presence of a previously known, homozygous, missense variant c.298T>A (p.Cys100Ser) in exon 3 of the CCN6 gene in all cases. Due to all three families belonging to the same community, analysis by Sanger sequencing in the remaining two cases for the variant mentioned earlier showed both cases to be of homozygous mutant genotype. Unaffected family members, i.e., parents and siblings, were either heterozygous carriers or wildtype for the said variant. The present case series is the first report of a recurrent variant occurring across multiple PPD-affected individuals from unrelated families belonging to the same community from India.

Congenital Pseudarthrosis of Femur and Sciatic Nerve Palsy with Congenital Constriction Band Syndrome: Report of the First Case in Literature.

Congenital constriction band syndrome has varied clinical presentations ranging from small, incomplete skin deep constriction band to in utero amputation. Pseudarthrosis of underlying bone most commonly tibia has been reported by many authors. We report the first case of congenital pseudarthrosis of the femur with congenital constriction band syndrome. Nine-day-old female presented with the constriction band in the left thigh with open pseudarthrosis of the femur. The left femur had gross recurvatum deformity and the posterior apex of the pseudarthrosis was exposed via skin ulceration. She had an ipsilateral paralytic clubfoot. She was treated with single-stage excision of constriction band and Z-plasty. Spontaneous union of the femur was achieved at 3 months. Procurvatum deformity of the femur improved gradually over 3 years. This happens to be the first and only reported case of congenital pseudarthrosis of the femur with sciatic nerve palsy due to congenital constriction band.

Bilateral Fracture Neck Femur in Child with Bilateral Delayed Union and Bilateral AVN: A Rare Occurrence and Literature Review.

A bilateral neck of femur fracture in children is a rare occurrence with only twelve cases reported till the date. We report a case of a 3-year-old schoolgirl with bilateral Delbet type 2 fracture neck femur after a fall from height. She was managed elsewhere by bilateral closed reduction and screw fixation within 24 h. She presented to us three months after surgery with painful hip movements and inability to walk. Her X-ray showed bilateral Ratliff type three avascular necrosis and bilateral delayed union with visible fracture lines. We placed her in double hip spica for three months. Fortunately, on both sides fractures united well with complete resolution of avascular changes. At one year follow-up, she had no functional limitation, no limb length discrepancy, and an x-ray showed mild coxa vara on left. Bilateral delayed union and avascular necrosis of fracture neck femur has not been reported till date.

Remodelling in Children's Fractures and Limits of Acceptability.

Remodeling follows inflammatory and reparative phases of bone healing and is very pronounced in children. Unlike adults, in growing children, remodeling can restore the alignment of initially malunited fractures to a certain extent, making anatomic reduction less essential. Remodeling is not universal and ubiquitous. Animal experiments and clinical studies have proven that in a malunited fracture, the angulation corrects maximally by physeal realignment (75%) and partly by appositional remodeling of the diaphysis also known as the cortical drift (25%). Remodeling potential reduces with the increasing age of the child; lower extremities have higher remodeling potential compared to the upper extremity. Remodeling is most pronounced at the growing end of the bone and in the axis of the adjacent joint motion. Correction of a very small amount of rotational malalignment is possible, but it is clinically not relevant. Overgrowth of the bone after a fracture occurs due to hyperaemia of fracture healing. Overgrowth is the most common after paediatric femur fractures, though it is reported after fractures of the tibia and humerus as well. The orthopaedic surgeon treating children's fractures should be familiar with regional variations of remodeling and limits of acceptance of angulation in different regions. Acceptability criteria for different bones are though well defined, but serve best as guidelines only. For the final decision-making patient's functional capacity, parents' willingness to wait until the completion of the remodeling process, and the experience of treating doctor should be considered concurrently. In case of the slightest doubt, a more aggressive approach should be taken to achieve a satisfactory result.

Usefulness of the Sauvegrain Method of Bone Age Assessment in Indian Children.

INTRODUCTION: Bone age estimation is very useful in children undergoing epiphysiodesis or guided growth surgery especially during the years of accelerated growth. It may be noted that no data are available on bone age estimation for Indian children of this age group. Sauvegrain (French) method is a very useful and simple method for bone age assessment during the years of accelerated growth. We decided to check the usefulness and the accuracy of the Sauvegrain method in Indian children. MATERIALS AND METHODS: A team of two pediatric orthopaedic surgeons and a radiologist scored elbow X-rays of 80 healthy children (40 boys and 40 girls), using the Sauvegrain method twice. Interobserver reliability and intraobserver reproducibility of the Sauvegrain scoring were assessed. RESULTS: There was a very strong correlation between all observers in both rounds (r = > 0.8) and an excellent reproducibility by the same observer in both rounds (r = 0.955). Chronological and bone age are considered the same if the difference between them is less than 6 months. With this criterion bone and chronological ages matched in > 37% of boys and girls, similar to the study done in French children. In the nonmatching group, more children had delayed bone age compared to their chronological age. CONCLUSION: The Sauvegrain method of bone age assessment described for French children was found to be useful in estimating bone age in Indian children. It is especially helpful in the clinical practice for detecting mismatch between the chronological and the radiological age before undertaking guided growth or epiphysiodesis.

Video Technique on Medial Open Reduction for DDH.

BACKGROUND: The most common approach for the open reduction of DDH is the anterolateral approach. After an initial report by Weinstein and Ponseti, the medial approach for DDH has garnered great interest. PURPOSE: The medial approach for DDH allows easy access to the structures which block the reduction of the femoral head into the acetabulum; namely the psoas tendon, inferior capsule, and ligamentum teres. It uses a skin crease small incision in the groin with excellent cosmetic outcome and is very well hidden. METHOD: The classical medial approach described by Ludloff uses interval between the adductor brevis and pectineus. The anteromedial approach to the hip uses the same incision but interval between the pectineus and femoral neurovascular bundle and allows better handling of medial circumflex vessels. A technical modification suggested by Late Ian Torode involves tenodesis of the ligamentum teres which improves the stability of the hip reduction. This video demonstrates the medial approach for the open reduction of DDH in a fourteen months old girl with medium-term follow-up results. The technique of the tenodesis of ligamentum teres is also shown. RESULT: The medial approach is safe with a low rate of re-dislocation; it does not violate the hip abductors and iliac apophysis. The major disadvantage of the medial approach is the restricted operative field and a higher rate of AVN. Many authors have found the rate of AVN comparable to other approaches and the grade of AVN milder culminating in good long-term results. CONCLUSION: We have found this approach very useful in children with DDH, before they start walking (when the closed reduction is unstable) and arthrogrypotic children with hip dislocation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43465-021-00502-6.

Functional improvement in patients with Sprengel's deformity following Modified Green's procedure and simplified clavicle osteotomy-a study of forty cases.

PURPOSE: Sprengel's deformity though rare is the most common congenital anomaly of the shoulder region. The aim of the study was to check the effectiveness of the modified Green's procedure with simplified clavicle osteotomy in providing significant functional and radiological improvement without neurovascular complications. METHODS: Sixty-eight children of Sprengel deformity were operated by the modified Green's release. Of which forty patients (15 male, 25 female) with more than two years follow-up were evaluated retrospectively. Simplified clavicle osteotomy was done in 34 patients. Severity was graded clinically by Cavendish grading (Grade II-6, III-34) and radiologically by Rigault grading (Grade II - 35, III - 5). The average age at surgery was 5.05 years with a mean follow-up of 62 (24-145) months. RESULTS: The average improvement in Cavendish grade was 2.6 grades, and Rigault grading was 1.07 grades. Shoulder abduction improved by a mean of 360. There was no neurovascular complication in children who had simplified clavicle osteotomy, and one patient without clavicle osteotomy developed transient brachial plexus palsy. Other complications were wound gape, pleural tear and scapular winging. CONCLUSION: The modified Green's procedure with simplified clavicle osteotomy allows for excellent correction of function and cosmesis. We describe a simpler technique of clavicle osteotomy that is quick, safe and equally effective in preventing neurovascular complications. We also describe a surrogate clinical test to avoid potential neurological injury in the absence of neuromonitoring. To the best of our knowledge, this is the second-largest operative series of Sprengel's deformity.

CT-Guided Percutaneous Drilling of Osteoid Osteoma: A Safe, Minimally Invasive and Cost-Effective Method.

BACKGROUND: CT-guided percutaneous drill resection (PDR) for osteoid osteoma fell out of vogue with the advent of radiofrequency ablation (RFA). However, the routine use of RFA is offset by its high cost and need for specialized instrumentation. AIMS AND OBJECTIVES: This study is an analysis of our series of patients treated with PDR, to know its efficacy, safety and cost-effectiveness. MATERIALS AND METHODS: This study is a retrospective analysis of prospectively collected data of 33 patients with a mean age of 10.03 years (2-21 years 13:10 M:F). The proximal femur was the commonest location, followed by shaft femur, tibial shaft, pubic ramus and lateral humeral condyle. Three were recurrences. The procedures were performed by one of four fellowship-trained paediatric orthopaedic surgeons, using a standard protocol with the help of a radiologist. CT-guided drilling was performed under sedation/short general anaesthesia using a guidewire for identification, followed by sequential drilling using a 6.5 mm cannulated drill or a triple ream drill. Patients were hospitalized overnight for pain relief and allowed protected weight bearing as per pain tolerance. They were evaluated weekly for 2 weeks and 3 monthly thereafter. RESULTS: The mean final follow-up was 19.72 months (6 months to 58 months). All patients had complete resolution of symptoms within 3 days of the procedure. There were no major complications and there were two minor complications (haematoma and cutaneous hypoaesthesia). There were no recurrences till the last follow-up. CONCLUSION: This study, one of the first and largest from India about CT-guided PDR, shows that this method can still be safely and effectively used as a primary treatment modality in OO, especially in economically challenged population. It is much more cost-effective than RFA, can be used even for recurrent tumours and can be safely be performed by a general orthopaedic surgeon without any special instrumentation.

Primary nonunion of the distal radius fractures in healthy children.

There are no published case series of nonunion of distal radius fractures in healthy children because of the rarity of its occurrence. We searched for all reported cases of this condition in Pubmed, Google scholar, and SCOPUS. We found three series, which included one previously reported by our group. The aim of the present study was to define the predisposing factors leading to nonunion after treatment of distal radius fractures in healthy children. We also aimed to emphasize that nonunion should be included in the list of complications of distal radius fractures in children and be mentioned in the textbook of pediatric trauma.