Ulnar Deficiency Research Articles

The Surgical Closure of Neglected Ulnar Deficiency of the Hand; Unclassified Phenomenon “Ulnar Cleft Hand”

The Surgical Closure of Neglected Ulnar Deficiency of the Hand; Unclassified Phenomenon “Ulnar Cleft Hand”

The One-Bone Forearm in Children: Surgical Technique and a Retrospective Review of Outcomes

The purpose of this study was to describe a technique of end-to-end rigid fixation of the distal radius to the proximal ulna. The shortening and radioulnar overlap in this technique yield a high union rate, large corrections, and few complications. This retrospective chart review from 2 centers was undertaken in 39 patients (40 forearms) who underwent one-bone forearm operations between 2005 and 2019. There were 25 male and 14 female patients, with a mean age at surgery of 9.7 years (range 3 to 19 years; SD, 4.5 years). The diagnoses included brachial plexus birth injury, spinal cord injury, arthrogryposis multiplex congenita, cerebral palsy, ulnar deficiency with focal indentation, multiple hereditary exostosis, acute flaccid myelitis, and tumor. The average follow-up was 33.5 months (1.2-110.1 months; SD, 27.1 months). The 36 forearms in supination had an average supination contracture of 93° (range, 15° to 120°; SD, 15.4°). The 4 pronated arms had an average pronation contracture of 80° (range, 50° to 120°; SD, 29.2°). The average postoperative position was 22.8° of pronation (range, -15° to45°; SD, 12.9°). The average correction obtained with our technique was 113° (range, 20° to 145°; SD, 22.9°). Radiographic union was demonstrated in 32 (80%) of the one-bone forearms by 10 weeks, 39 (97.5%) by 16 weeks, and 40 (100%) by 24 weeks. One patient had peri-implant fractures prior to union. No forearms required reoperation for nonunion. One-bone forearm performed with this technique allows reliable healing and a large degree of correction. Therapeutic IV.

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.

Severity of ulnar deficiency and its relationship with lower extremity deficiencies.

To assess the characteristics of ulnar deficiency (UD) and their relationship to lower extremity deficiencies, we retrospectively classified 82 limbs with UD in 62 patients, 55% of whom had femoral, fibular, or combined deficiencies. In general, UD severity classification at one level (elbow, ulna, fingers, thumb/first web space) statistically correlated with similar severity at another. Ours is the first study to show that presence of a lower limb deficiency is associated with less severe UD on the basis of elbow, ulnar, and thumb/first web parameters. This is consistent with the embryological timing of proximal upper extremities developing before the lower extremities.

Soft-Tissue Distraction Prior to Single Bone Forearm Surgery in Ulnar Longitudinal Deficiency: A Report of Two Cases

Ulnar longitudinal deficiency (ULD) is a rare congenital disease of the upper limb. The deformities caused by ULD can be very challenging and may compromise hand function during daily activities. Although the first surgical intervention dates back to the year 1952 there is still no gold standard for treating this uncommon disorder. Two children aged 16 and 3 years with ULD Bayne Type II (partial ulna aplasia) were diagnosed and treated at our department with single bone forearm surgery to achieve stability and improve function using a modified surgical method. For the purpose of an additional gain in limb length and improved cosmesis we used an Ilizarov external fixator for soft tissue distraction including radius distalization prior to the creation of the single bone forearm. This new technique and results are presented and discussed.

Congenital Upper Limb Differences Registry: Development and Challenges of a Prospective Database

There is no financial information to disclose. To improve upon the traditionally retrospective case series of congenital upper limb differences, a prospective cohort multi-center registry for Congenital Upper Limb Differences (CoULD) was created. The hypothesis for the current study is that demographics and clinical presentation of patients in the CoULD registry will be different than other cross-sectional or epidemiological studies. The CoULD registry includes preoperative children from 0 to 18 years of age with a congenital upper extremity difference. Demographic information and prenatal history are collected. Congenital differences are classified using the Oberg-Manske-Tonkin (OMT) classification. For the present study, data from two centers in the CoULD registry was analyzed over a 27- month period. There were a total of 910 differences in 853 patients. Median age at enrollment was 2.9 years (IQR 0.7-8.5). Two-hundred four children (27%) had a positive family history and 241 (32%) had pregnancy-related risk factors. Three-hundred forty-seven (41%) patients had bilateral involvement. Additional orthopedic conditions were registered in 29% (213) and medical comorbidities existed in 30% (221) of subjects. According to OMT group, there were 780 malformations (86%), the majority affecting the hand plate only; 17 deformations (1.8%) and 113 dysplasias (12%). In addition 99 patients (12%) presented with a syndrome, most commonly amniotic constriction bands (Table 33-1). Significant differences were noted in pathologies according to age. Radioulnar synostosis, Madelung deformity, congenital dislocation of the radial head and osteochondromatosis presented almost exclusively in children older than 2 years (P ≤ 0.01); conversely polydactyly, radial longitudinal deficiency and syndactyly presented more commonly in younger patients. Compared with a cross-sectional study (1), CoULD included more pathologies of late presentation and those that do not commonly require surgical care. Similarly, when compared with a retrospective population study (2), CoULD captured more late presenting conditions but did not include the same proportion of pathologies with early surgical treatment (Table 33-2). •Congenital differences present at characteristic ages; the prospective cohort design of the CoULD registry offers the advantage of including a broad spectrum of pathologies including those of late presentation.•This study highlights the differences in prevalence of these conditions found with different study types. CoULD identified more late-presenting and non-operative conditions such as symbrachydactyly, radioulnar synostosis, and transverse deficiency, than other study types.•The CoULD registry will provide a more complete description of the prevalence of congenital upper limb differences presenting in a clinical environment and will offer the opportunity to better characterize this pediatric population.Table 33-1Relative Frequency of Congenital Upper Limb Differences of Patients Enrolled in the CoULD Registry by OMT Classification GroupsOMT GroupsCoULD Total< 2 years> 2 yearsP value(n = 910)%(n = 397)%(n = 525)%I. Malformations A. Malformations Entire Limb3403712131219430.02 B. Malformations Hand Plate440492516318937< 0.001II. Deformations172123510.030III. Dysplasias1131213310019< 0.001(n = 853)%(n = 372)%(n = 481)%IV. Syndromes9912401159120.49 Open table in a new tab Table 33-2Abstract of Key Differences in Relative Frequency of Congenital Upper Limb AnomaliesCoULDGoldfarb et al1P value(n = 897)%(n = 653)%I. Malformation ii. Symbrachydactyly – entire limb597%71%< 0.001 i. Radial longitudinal deficiency374%437%0.01 iv. Radioulnar synostosis597%122%< 0.001 vii. Madelung deformity192%40.7%0.03 iv. Arthrogryposis475%539%0.01 ii. Symbrachydactyly – hand384%417%0.02 iii. Transverse deficiency – hand20.2%224%< 0.001 ii. Camptodactyly556%214%0.03 iv. Distal arthrogryposis202%50.8%0.04 ix. Phalangeal synostosis80.9%00.0%0.02 xi. Cleft hand202%325%0.001II. Deformations 1. Constriction ring syndrome162%295%< 0.001III. Dysplasias i. Osteochondromatosis586%5710%0.03 ii. Enchondromatosis131%20.3%0.03IV. Syndrome9912%10917%< 0.001CoULDEkblom et al2P value(n = 687)%(n = 462)%I. Malformation ii. Symbrachydactyly – entire limb599%153%< 0.001 i. Radial longitudinal deficiency375%112%0.01 ii. Ulnar longitudinal deficiency264%41%0.001 iv. Radioulnar synostosis599%31%< 0.001 ii. Symbrachydactyly386%00%< 0.001 ii. Ulnar deficiency – hand101%163%0.02 iii. Radial polydactyly588%5913%0.02 v. Ulnar polydactyly416%9220%< 0.001 v. Clinodactyly365%398%0.03 ix. Phalangeal synostosis81%00%0.02 x. Synpolydactyly – central71%163%0.001IV. Syndrome9912%142%< 0.001 Open table in a new tab

Oligodactyly with Thumb.

Oligodactyly of the hand is one of the rarest congenital anomalies of upper extremities and defined as the presence of fewer than five fingers on a hand. Although it usually occurs in association with hypoplasia or absence of ulna, it can occur without abnormality of the forearm bones. The purpose of this study is to present clinical features and radiographic characteristics of hand oligodactyly with thumb. Five patients of oligodactyly with thumb who showed normal forearm bones, were evaluated. Two patients had threefingered hand with thumb, and three had two-fingered hand with thumb. We analyzed associated abnormalities of carpal and metacarpal bones and measured the lengths of radius and ulna, and width of the wrist on the simple radiographs. We also devised new classification system of oligodactyly based on the thumb deformities and locations of missing digits. Syndactyly among fingers was associated in four patients, clinodactyly caused by delta bone in one, hypoplasia of the thumb in one, camptodactylies in one, symphalangism in one, and radial head dislocation in one. Considering the abnormalities of the carpal bones, the missing digits were presumed to be ulnar-sided digits in two patients, central digits in one patient and both ulnar-sided and central digits in two patients. In patients with missing of central digits, an adjacent metacarpal was hypertrophied. Although the ulnar variances were within normal range, the average lengths of radius and ulna were 6% and 5% shorter than those of contralateral normal side. The average width of the wrist was 9% narrower than that of contralateral normal side. Syndactyly and hypertrophied metacarpal were most commonly observed findings in the oligodactyly with thumb. Although oligodactyly with thumb may be a type of ulnar longitudinal deficiency, however, it can also be a type of central deficiency or combined type of ulnar longitudinal deficiency with central deficiency or radial longitudinal deficiency. We suggest a classification system of oligodactyly with thumb based on locations of missing digits and associated thumb deformities.

Case report of congenital right ulnar deficiency

Case report of congenital right ulnar deficiency

An Overview of Treatments for Congenital Forearm Longitudinal Deficiencies

Summary Introduction. Congenital anomalies are rare, affecting 1-2% of new-borns and only 10% of them have upper limb defects. Incidence of forearm longitudinal deficiencies is 1:55 000-1:100 000 live births which means that 1 case in every two to four years can be expected in Latvia. Centralisation surgical procedure was the main treatment option until 2008, but it had the worst functional outcome (as literature data also show). Starting from 2010, several new surgical techniques like microvascular metatarsophalangeal joint transfer, epiphyseal fibula flap transfer and wrist radialisation had been performed in the Microsurgery Centre of Latvia. Aim of the study. A retrospective study to collect and assess functional outcomes of different types of surgeries. Material and Methods. 5 patients (7 hands) with radial club hand deformity, one ulnar club hand deformity and one ulnar dimelia were treated in the Microsurgery Centre of Latvia from 2012 to 2014. The Paediatric Evaluation of Disability Inventory (PEDI) was used to evaluate functional outcome in children. ROM (range of motion), pinch and grasp forces were measured to establish wrist motion and stability. Visual analogue scale (VAS) was used to evaluate parents’ satisfaction. Results. 3 patients (5 hands) were selected for the trial. Two patients (3 hands) were not evaluated as thumb reconstruction is not done yet. Patients had a small (10-25°) reoccurrence of radial deviation after centralisation and radialisation procedures, whereas MTP (metatarsophalangeal) joint transfer patients had straight wrists. Wrist joint functionality in MTP patients was following: extension of 10°-35° and flexion of 20°-90°. In MTP transfer patients, PEDI score was 56-58 for daily activities (normal score – 50), 69-70 for mobility (normal score – 63). VAS score was greater for MTP joint transfer patients. Conclusion. Radial and ulnar deficiencies are rare and reconstructions should be done at age 2 - 4 years, because late reconstructions are more complicated due to the stiffness of the radial fingers. Radialisation procedure is the first choice for wrist stabilization, but, in some cases, MTP joint transfer or vascularised fibular head transfer can provide a better functional outcome in radial club hand patients.

Unilateral Ulnar Deficiency with Monodactyly: A Case Report

Ulnar deficiency, a complex spectrum of postaxial forearm and hand abnormality, is an infrequently encountered, highly variable, reduction defect1. It can be defined as a congenital anomaly characterized by missing or foreshortened upper limb resulting from a disturbance in embryonic development affecting the ulnar side2.

Congenital deficiency of distal ulna and dislocation of the radial head treated by single bone forearm procedure.

Congenital deficiency of part of distal ulna affecting the distal radio-ulnar joint is a rare disorder. It is even rarer to find the association of proximal radio-ulnar joint dislocation along with distal ulnar deficiency. This type of congenital forearm anomaly is difficult to treat. Conversion to a single bone forearm in the expense of pronation-supination movement is a viable option. By doing so the elbow and wrist can be stabilized; however movement is possible in only one plane. We are describing here a girl of 8 years having proximal radio-ulnar joint dislocation along with deficiency of distal ulna treated by converting into a single bone forearm.

A New Documentation System for Congenital Absent Digits

Congenital absent digits continue to be described by many confusing terms and are currently classified in categories I, V, and VI of the International Federation of Societies for Surgery of the Hand classification and seven subclassification systems. Very few classification systems provide any logical basis for surgical reconstruction. The purpose of this study was to develop a simple alphanumerical documentation system to reproducibly describe the morphological or radiographic appearance of congenital absent digits and facilitate communication of these childrens' hand anomalies from one hand surgeon to another. Dorsal and palmar photographs and PA radiographs of 235 hands in 204 children born with congenital absent digits over a 15-year period were analyzed to determine which digital rays were missing and their level of absence. Each hand can be described by three letters, R (radial), C (central), and U (ulnar), as well as numbers 1-5. The first letter and number designate which rays are missing and the second and third letters and numbers designate which rays remain present. There are 15 morphological phenotypes of congenital absent digits. The three most common phenotypes are U4R1 (a thumb but absence of all four fingers), R1U4 (absent thumb), and R5 (aplastic hand). This new documentation system allows hand surgeons to describe the simple morphological or radiographic appearance of congenital absent digits; incorporates all the previous subclassification systems that have attempted to describe congenital absent digits in radial, central, and ulnar deficiencies, symbrachydactyly, and congenital constriction ring syndrome; and has subsequently allowed the development of an algorithm which predicts whether conventional or microsurgical reconstruction is indicated for each specific phenotype.

Thumb in the Plane of the Hand: Characterization and Results of Surgical Treatment

The purpose of this retrospective investigation is to characterize a congenital deformity, the thumb in the plane of the hand (TPH), and to evaluate the results of abduction-rotation osteotomy of the thumb metacarpal with thumb web space deepening (WSD). We performed a comprehensive analysis of the medical records, hand therapy notes, and radiographs to evaluate clinical features of the TPH deformity. We evaluated clinical and radiographic outcomes and incidence of deformity recurrence after abduction-rotation osteotomy and thumb WSD. Thirteen patients (7 girls and 6 boys) with 14 affected hands treated with an abduction-rotation osteotomy of the thumb metacarpal and formation of a deepened thumb-index web space met inclusion criteria. All TPH deformities were associated with other congenital conditions, including symbrachydactyly, syndactyly, central deficiency, and ulnar deficiency. During the course of treatment, patients had a mean of 4 surgeries per hand; 3 hands required osteotomy revision with or without revision WSD, and 6 additional hands required revision of thumb WSD alone. None of the affected hands were capable of thumb opposition to any finger before surgery, whereas after surgery, all 14 hands could actively perform key pinch, and 9 of the 14 hands could actively oppose the thumb to at least 1 finger. The TPH deformity occurs in association with other congenital abnormalities of the hand. An abduction-rotation osteotomy of the thumb metacarpal with thumb WSD can restore thumb opposition and improve function; nonetheless, multiple surgical procedures are often required, and thumb function may remain limited. Therapeutic IV.

Combined Congenital Radial and Ulnar Longitudinal Deficiencies: Report of 2 Cases

Variation in longitudinal deficiencies is likely related to the timing and duration of an insult during early limb development. In experimental models, teratogenic insults induce ulnar deficiencies earlier in gestation than radial deficiencies. In this report, we describe the rare combination of right radial and left ulnar deficiencies in 2 cases. Interestingly, 1 case had a history of 2 separate and apparently distinct episodes of bleeding during early gestation, whereas the other demonstrated associated hematoma formation early in development. These cases also demonstrate the susceptibility for ulnar defects on the left and radial defects on the right. The authors discuss the relationship of prenatal insults on limb development and the mechanisms underlying longitudinal deficiencies.

Ulnar focal cortical indentation

Deformity of the forearm due to growth disturbance of the ulna occurs in a number of conditions such as ulnar deficiency, multiple exostoses, and neurofibromatosis. We report a previously unrecognised form, caused by focal cortical indentation. We have treated five children with this condition, three girls and two boys; the mean age at presentation was 5 years (2 to 8). The deformity was first recognised about the age of two years, and progressed gradually. The radiological findings were the same in all cases. The focal cortical indentation was seen at the distal end of the ulna with anteromedial bowing and dysplasia. The radial head was dislocated posterolaterally. In one patient the histological findings at the site of indentation were of a fold of tissue resembling periosteum, which interfered with enchondral ossification. Treatment by ulnar lengthening using an external fixator and osteotomy which corrected both the ulnar deformity and reduced the dislocated radial head in two cases gave the best results.

Protection from ethanol-induced limb malformations by the superoxide dismutase/catalase mimetic, EUK-134.

Based on previous in vitro studies that have illustrated prevention of ethanol-induced cell death by antioxidants, using an in vivo model, we have tested the anti-teratogenic potential of a potent synthetic superoxide dismutase plus catalase mimetic, EUK-134. The developing limb of C57BL/6J mice, which is sensitive to ethanol-induced reduction defects, served as the model system. On their ninth day of pregnancy, C57BL/6J mice were administered ethanol (two intraperitoneal doses of 2.9 g/kg given 4 h apart) alone or in combination with EUK-134 (two doses of 10 mg/kg). Pregnant control mice were similarly treated with either vehicle or EUK-134, alone. Within 15 h of the initial ethanol exposure, excessive apoptotic cell death was observed in the apical ectodermal ridge (AER) of the newly forming forelimb buds. Forelimb defects, including postaxial ectrodactyly, metacarpal, and ulnar deficiencies, occurred in 67.3% of the ethanol-exposed fetuses that were examined at 18 days of gestation. The right forelimbs were preferentially affected. No limb malformations were observed in control fetuses. Cell death in the AER of embryos concurrently exposed to ethanol and EUK-134 was notably reduced compared with that in embryos from ethanol-treated dams. Additionally, the antioxidant treatment reduced the incidence of forelimb malformations to 35.9%. This work illustrates that antioxidants can significantly improve the adverse developmental outcome that results from ethanol exposure in utero, diminishing the incidence and severity of major malformations that result from exposure to this important human teratogen.

Teratogenic mechanisms of longitudinal deficiency and cleft hand.

In order to better understand the teratogenic mechanisms of congenital defects of the digits, we analyzed clinical cases and induced similar types of congenital hand anomalies in rat fetuses by oral administration of busulfan. In clinical cases, radial and ulnar deficiencies had common characteristic features. We induced radial and ulnar deficiencies in rat fetuses with the same drug. Radial and ulnar deficiencies induced in rats have similar clinical manifestations and these anomalies might be caused by the same teratogenic mechanism. Then, the formation of the digital rays was examined histologically. The results of histological examination suggested that these deficiencies were not caused by localized damage of the limb bud. They also suggested that the cause of missing digits in longitudinal deficiency is closely related to a deficit of mesenchymal cells in the limb bud. Cleft hand is considered to be one of the types of longitudinal deficiency. However, several investigators have suggested that the abnormal induction of finger rays in the process of formation of fingers induced central polydactyly, osseous syndactyly and also cleft hand. X-rays of the clinical cases and skeletal changes of the anomalies induced in rats appear to demonstrate that cleft hand formation proceeds from osseous syndactyly and central polydactyly. The results of our experimental study show that the critical periods of central polydactyly, osseous syndactyly and cleft hand are the same. They also suggest that central polydactyly, syndactyly and cleft hand might be induced when the same teratogenic factor acts on embryos at the same developmental stage in the human being. Because they have a similar causation, cleft hand, syndactyly and central polydactyly should be classified into the same entity, that is, abnormal induction of digital rays. Based on these clinical and experimental studies, we modified the Swanson classification. In our modified classification, typical cleft hand, syndactyly and polydactyly are included in the same category of abnormal induction of digital rays as the fourth new category.

The ulnar longitudinal deficiency. New classification based on a review of 46 cases

The ulnar longitudinal deficiency. New classification based on a review of 46 cases

Classification of ulnar deficiency according to the thumb and first web

Fifty-five ulnar-deficient upper extremities in 45 patients treated at the St. Louis Shriner's Hospital were reviewed in order to evaluate the hand abnormalities. Thumb and first-web abnormalities were noted in 73% of hands. The majority of operations (28 of 53) were recommended to improve functional deficits associated with abnormalities of the thumb and first web. A classification of the ulnar-deficient hand based upon the characteristics of the thumb and first web is presented. When used in combination with any of the six current forearm/elbow classification schemes, this classification more completely describes ulnar deficiency of the upper extremity. Four classification types are proposed based upon progressive involvement of the thumb and first web. In type A, the thumb and first web are normal; in type B, the first web space has mild deficiency and the thumb has mild involvement. Extrinsic tendon function is intact and opposition function is present. In type C, the thumb has varying degrees of involvement. The first web has moderate to severe deficiency, including thumb-index syndactyly, and is often associated with malrotation of the thumb into the plane of the other digits, loss of opposition, and dysfunction of the extrinsic tendons. In type D, the thumb is absent. Previous classifications of ulnar deficiency neglect the radial hand anomalies that have been noted by several authors in a high percentage of affected extremities. Our premise for this classification is that the thumb and first-web abnormalities are related to the complexity of the hand problem and that the frequently noted radial hand abnormalities require the majority of surgical procedures. Such a classification based on the thumb and first-web deformities will focus the surgeon's attention on those deficiencies that are most important for the restoration of function. It is proposed that ulnar deficiency be classified by one of the classification schemes that describes the anatomy of the forearm and/or elbow supplemented by the hand classification type.

Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Longitudinal Failure of Upper-Limb Formation*†

Failure of formation of the structures of the upper extremity presents as longitudinal or transverse deficiencies of the embryonic limb bud. The deficiencies that develop along longitudinal axes are classified as radial, central, or ulnar. Use of the once commonly employed terms pre-axial and post-axial for describing longitudinal deficiencies is discouraged as these terms do not include the concept of central defects. It is tempting to speculate that these axially oriented failures of formation are the result of teratogenic insults or genetic influences that destroy cells at specific locations on the apical ectodermal ridge or the supporting mesoderm of the embryonic limb bud7. Although this is true for radial deficiencies, which characteristically affect only the structures on the radial border of the forearm and hand, the cause of ulnar and central deficiencies is not as clearly defined. Ulnar deficiency may include dysplasia of the thumb and the radial rays in addition to the ulnar structures. Central deficiency (cleft hand) is frequently associated with polydactyly (duplication) or syndactyly (failure of differentiation), or both, of the central digits. These more complex presentations suggest that the concept that deficiencies of the upper extremity are related to focal limb-bud-cell destruction is too simplistic. Nevertheless, it provides a basis for categorizing and discussing the clinical presentations. Radial deficiency describes a spectrum of osseous, musculotendinous, and neuromuscular dysplasias of the radial border of the upper limb69. Kato et al.35 produced varying degrees of radial deficiency by administering Myleran (busulfan) to pregnant WKAH/Hkm rats at nine to 11.5 days of gestation. The extent of the deficiencies was dose-related and resembled that of deficiencies seen in humans. Associated skeletal, hematological, cardiac, renal, and gastrointestinal defects24,27,28,32,71,79,87 may be overlooked initially because …