Phocomelia

                                   Dr. KS Dhillon

Introduction

Phocomelia (fig 1) is a rare congenital disorder. It is defined by the absence of intermediate segments of the extremity. In children with phocomelia, the hands or feet are directly attached to the trunk. Phocomelia is a teratogenic side effect of the drug thalidomide. This drug was first marketed to treat anxiety and morning sickness. There were claims that the drug was safe during pregnancy. It was however removed from the market in the 1960s when doctors noted an association with phocomelia. About 40% of patients affected by the teratogenic effects of thalidomide die near the time of birth. These congenital disabilities had a profound political and social impact on drug regulation and proof of safety (1,2).

Fig 1.

Etiology

Phocomelia is the most notable side effect of thalidomide. In the last 30 years, there have been several cases of phocomelia associated with thalidomide use. Today however the cause of most cases is undetermined. Despite strict regulation worldwide, there have been several cases of phocomelia attributed to thalidomide. Underdeveloped countries and those that are endemic with leprosy where thalidomide remains in use, still report cases of defects caused by thalidomide exposures in pregnancy. In more developed countries with strict regulations, there has been a dramatic decrease in the incidence of phocomelia within the general population (3,4).

Besides the teratogenicity of thalidomide, researchers have hypothesized that phocomelia is associated with anomalous origins of the subclavian artery. This results in a disrupted vascular supply to intermediate limb segments (5,6).

Epidemiology

Bermejo-Sanchez et al (1) examined 22,740,933 live births to study the incidence and presentation of phocomelia to assess the prevalence of true phocomelia. According to reports true phocomelia occurs in 0.62 live births per every 100,000 births. About half (53.2%) of the cases displayed isolated phocomelia, 36.9% had additional major congenital abnormalities, and 9.9% of cases correlated with a clinical syndrome. 

According to the data one limb was involved in 55.9% of the cases, while in 40.2% of cases, two limbs were involved. Of the 141 cases, only four cases had involvement of all four limbs. When single upper limb deficiencies are compared, the left side is more commonly affected (64.9%) than the right side. When two limbs are involved, the upper limbs are involved 58.5% of the time compared to the lower limbs (1,7). 

Pathophysiology

When the extremity develops, the apical ectodermal ridge forms at the most distal end of the limb bud. This apical ectodermal ridge, through its interaction with the underlying progress zone mesoderm, determines the appropriate longitudinal growth of the extremity and differentiation of the limb bud's distal and proximal structures. Cell death due to apoptosis from any cause such as drug toxicity or vascular insufficiency that interrupts this relationship between the apical ectodermal ridge and the progress zone can produce phocomelia (8).

History and Physical Examination

Whenever phocomelia is identified in a newborn, given its correlation with thalidomide, doctors should inquire about medications taken during early pregnancy. Children with phocomelia should undergo a thorough physical examination since one study reported that 36.9% of phocomelia cases have additional major malformations, with 9.9% of cases being attributable to various syndromes (1).

Evaluation

In children when phocomelia is identified, the doctors should complete a thorough search for other associated abnormalities. Other defects are present in approximately half of the patients with this limb anomaly. Doctors should examine the musculoskeletal system, including the heart, vertebrae, and intestines, as dysfunction in these organ systems appears most frequently in conjunction with phocomelia (1).

Management

In the management of children born with phocomelia, it is important to look for other associated abnormalities, especially of the intestines and heart, and address them promptly. Gastroenterologists and pediatric cardiologists should examine the child and recommend a treatment plan for abnormalities encountered.

For patients with hypoplastic limbs, prosthetics may be of some value. Many without concomitant pathology can function quite well. Families of children with severely hypoplastic extremities should work with therapists to meet the unique needs of their children. Caring for a disabled child can be traumatic for some people. Hence, physicians should have a low threshold to recommend mental counseling services to assist in coping mechanisms that may be needed by both the child and the parents.

Differential Diagnosis

Bermejo-Sanchez et al (1) reported that 9.9% of cases of phocomelia are associated with different syndromes. They are listed here in order of decreasing prevalence:

1. Roberts Syndrome: A rare autosomal recessive disorder caused by a mutation in the ESCO2 gene that manifests with severe limb malformations and craniofacial defects (9).

2. Thrombocytopenia with radial aplasia (TAR): A rare autosomal recessive disorder related to the RBM8A gene that presents with thrombocytopenia and limb radial deficiency (10).

3. Syndrome of severe limb defects, vertebral hypersegmentation, and mirror polydactyly: An autosomal recessive disorder resulting in severe limb hypoplasia with polydactyly and hypersegmentation of the spine (11).

Prognosis

In a review study by Bermejo-Sánchez, there were 85 live births to every 24 stillbirths for children with phocomelia. In patients with isolated phocomelia, there were 57 live births to every eight stillbirths (1).

Complications

Children with phocomelia have a higher stillbirth rate as compared to the general population. Children with severe limb hypoplasia may face problems with mobility and activities of daily life. 

Patient Education

The incidence of thalidomide-induced limb hypoplasia has significantly reduced due to increased drug regulatory practices across the world. Thalidomide can be used for the treatment of insomnia, anxiety, and even leprosy. It is important to understand the risks of thalidomide exposure during pregnancy for any woman taking the medication. Patients and doctors should understand the deleterious effects of thalidomide when taken in early pregnancy.

Conclusion

In the regulatory practices of pharmacology, phocomelia and the thalidomide controversy were critical steps forward. The most important responsibility of the healthcare community with regards to phocomelia, is the prevention of prescribing unsafe medications that can cause limb truncation. This can be done through careful prescribing practices and patient education.

For patients born with limb hypoplasia, including phocomelia, an interdisciplinary team of specialists needs to examine the patient. This team can screen patients for associated abnormalities that may be fatal since half of the patients with phocomelia and amelia have associated defects. Many related abnormalities of the vertebrae, heart, or other vital organs may be life-threatening. These anomalies should be addressed promptly by the physicians. If surgical intervention is required, the dedicated OR team must be well-versed with the operative plan and work efficiently to optimize patient outcomes.

A prosthetist and therapist can help a developing child with disabilities to function at a higher level. Families of these disabled children are often under tremendous financial and emotional strain. Hence, appropriate mental health counseling and social work may be necessary to care for the patient and their families.

References

1. Bermejo-Sánchez E, Cuevas L, Amar E, Bianca S, Bianchi F, Botto LD, Canfield MA, Castilla EE, Clementi M, Cocchi G, Landau D, Leoncini E, Li Z, Lowry RB, Mastroiacovo P, Mutchinick OM, Rissmann A, Ritvanen A, Scarano G, Siffel C, Szabova E, Martínez-Frías ML. Phocomelia: a worldwide descriptive epidemiologic study in a large series of cases from the International Clearinghouse for Birth Defects Surveillance and Research, and overview of the literature. Am J Med Genet C Semin Med Genet. 2011 Nov 15;157C(4):305-20. 

2. Ridings JE. The thalidomide disaster, lessons from the past. Methods Mol Biol. 2013;947:575-86.

3. Castilla EE, Ashton-Prolla P, Barreda-Mejia E, Brunoni D, Cavalcanti DP, Correa-Neto J, Delgadillo JL, Dutra MG, Felix T, Giraldo A, Juarez N, Lopez-Camelo JS, Nazer J, Orioli IM, Paz JE, Pessoto MA, Pina-Neto JM, Quadrelli R, Rittler M, Rueda S, Saltos M, Sánchez O, Schüler L. Thalidomide, a current teratogen in South America. Teratology. 1996 Dec;54(6):273-7.

4. Schuler-Faccini L, Soares RC, de Sousa AC, Maximino C, Luna E, Schwartz IV, Waldman C, Castilla EE. New cases of thalidomide embryopathy in Brazil. Birth Defects Res A Clin Mol Teratol. 2007 Sep;79(9):671-2. 

5. van der Horst RL, Gotsman MS. Anomalous origin of the subclavian artery associated with phocomelia. S Afr Med J. 1971 Dec 18;45(48):1397-9. 

6. Bavinck JN, Weaver DD. Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Möbius anomalies. Am J Med Genet. 1986 Apr;23(4):903-18.

7. Källén B, Rahmani TM, Winberg J. Infants with congenital limb reduction registered in the Swedish Register of Congenital Malformations. Teratology. 1984 Feb;29(1):73-85.

8. Knobloch J, Rüther U. Shedding light on an old mystery: thalidomide suppresses survival pathways to induce limb defects. Cell Cycle. 2008 May 01;7(9):1121-7.

9. Ismail S, Essawi M, Sedky N, Hassan H, Fayez A, Helmy N, Shehab M, Farouk D, Elruby M, Otaify G, Eldarsh A, Hosny L, Gaber K, Aboul-Ezz EHA, Ramzy MI, Mehrez MI, Hassib NF, Elhadidi SMA, Aglan MS, Temtamy SA. ROBERTS SYNDROME: CLINICAL AND CYTOGENETIC STUDIES IN 8 EGYPTIAN PATIENTS AND MOLECULAR STUDIES IN 4 PATIENTS WITH GENOTYPE/PHENOTYPE CORRELATION. Genet Couns. 2016;27(3):305-323. 

10. Al-Qattan MM. The Pathogenesis of Radial Ray Deficiency in Thrombocytopenia-Absent Radius (TAR) Syndrome. J Coll Physicians Surg Pak. 2016 Nov;26(11):912-916. 

11. Urioste M, Lorda-Sánchez I, Blanco M, Burón E, Aparicio P, Martínez-Frías ML. Severe congenital limb deficiencies, vertebral hypersegmentation, absent thymus and mirror polydactyly: a defect expression of a developmental control gene? Hum Genet. 1996 Feb;97(2):214-7.

 

            Medial Ulnar Collateral Ligament Injury

                              Dr. KS Dhillon

Introduction

The medial ulnar collateral ligament (MUCL), also referred to as the medial collateral ligament (MCL), ulnar collateral ligament (UCL), and anterior bundle (AB) is the primary restraint to valgus instability of the elbow (1-5). The MUCL is one of three ligaments that comprise the “medial ulnar collateral ligament complex” of the elbow. The posterior bundle (PB) and transverse ligament (TL) are the other two (Fig 1). 

Fig 1.

The MUCL is the primary stabilizer of the elbow during valgus stress, followed by the radial head and dynamic stabilizers of the elbow such as the flexor-pronator muscle mass (6-10). The MUCL is composed of two separate bands (posterior and anterior) that provide reciprocal function with the posterior band tight in flexion, and the anterior band tight in extension. 

The MUCL is commonly injured in overhead-throwing athletes when a valgus moment is placed on the elbow during the early acceleration and late cocking phases (11-15). Incompetence or rupture of the ligament leads to valgus instability of the elbow which has varying clinical presentations. Patients may complain of instability, most however will report pain, reduced accuracy, and decreased velocity. Clinically significant pathology usually requires surgery. Appropriate graft positioning at both the humeral origin and the ulnar insertion is necessary when doing ligament reconstruction. A thorough understanding of the native anatomy of the MUCL facilitates the surgeon’s ability to restore stability and function effectively.

Morrey and An (10) in 1985 were the first to publish the quantitative analysis of the medial ulnar collateral ligament complex. They dissected 10 fresh frozen cadavers and described the dimensions of the AB and PB at various degrees of elbow flexion. Since then, multiple studies have assessed the anatomy and biomechanics of the AB (2,3,6,16,17). In the past general consensus held that the AB inserts solely and directly onto the sublime tubercle. Recent studies however have shown that the AB insertion is in fact broader, tapered, and significantly larger in terms of surface area. 

Anatomy

The MUCL (AB) is the primary restraint to valgus instability of the elbow (1-5). The PB is a soft tissue stabilizer of the elbow with greatest contributions during flexion (17). It is generally believed that the TL does not provide a significant contribution to elbow stability (10). A recent study however has revealed a direct insertion of the TL onto the AB that may potentially play a role in elbow stability (18). The AB, in particular, is the primary stabilizer of the elbow in valgus stress, with the radial head and dynamic stabilizers of the medial elbow also contributing (6-10). It originates on the anterioinferior surface of the medial epicondyle and goes on to insert on the sublime tubercle of the ulna (Fig 1).

Origin

Surface area and footprint center: The origin of the AB is posterior to the elbow’s axis of rotation. It is on the anterior, inferior, and lateral aspect of the medial epicondyle (10). The surface area of the humeral origin has been widely variable. Dugas et al (19) carried out a study in 13 fresh frozen cadavers utilizing a three-dimensional (3-D) electromagnetic tracking and digitalizing device and showed that the AB origin was round with a mean surface area of 45.5 mm2 (range of 25.9-59.4 mm2). A recent study by Camp et al (18) found a mean origin surface area of 32.3 mm2. In contrast to these two studies, Frangiamore et al (20) also studied 10 fresh frozen cadaver specimens and found the measurement to be notably smaller at 17.0 mm2 (range of 14.9-19.1 mm2). It is possible that due to differences in measurement techniques, these studies demonstrated variable results. 

Frangiamore et al (20) and Dugas et al (19) described the center of the ligament origin in different terms. This is of clinical importance when determining the location of humeral tunnel placement during MUCL reconstruction surgery. Dugas et al (19) described the center of the origin in an area on a flat surface anterior and inferior to the medial epicondyle. The mean distance they measured was 13.4 mm from the center of the medial epicondyle to the center of the origin. Camp et al (18) found a similar mean distance of 11.7 mm. Frangiamore et al (20) described this measurement in terms of two separate measurements. They reported the center of the origin to be located, on average, 8.5 mm distal (inferior) and 7.8 mm lateral (anterior) to the medial epicondyle. 

Insertion

Surface area and footprint center: The ulnar footprint of the AB inserts solely onto the sublime tubercle. It serves as the anatomical landmark for surgical repairs and reconstructions. In one early report, the mean AB insertional surface area was 66.4 mm2 (20).

Recently some authors have described the AB insertion as a longer, distally tapered area that follows the ulnar ridge. Dugas et al (19) reported that the surface area of this broader insertion has a mean surface area of 127.8 mm2. They found that the length of the ulnar footprint measured an average of 29.2 mm. Other authors have found similar lengths of tapered insertion with means of 30.2 mm and 29.2 mm (21,22). Camp et al (18) found a tapered insertion with a mean surface area of 187.6 mm2 and an ulnar footprint length averaging 29.7 mm.

Since the footprint center of a broader tapered insertion may not occur in the location previously assumed at the apex of the sublime tubercle, the optimal position of the ulnar tunnel in reconstructive surgery may still need to be elucidated. The clinical relevance of the broader tapered ulnar insertion described in studies by Camp et al (18) and Dugas et al (19) requires further investigation.

A study of 10 cadaveric specimens by Camp et al (18) has shown the mean proximal insertional width to be 9.4 mm which is greater than previously reported (18). This discrepancy in widths leaves room for further investigation. 

Overall ligament dimensions

Length: The AB is the longest ligament of the medial elbow. It spans the inferior aspect of the medial epicondyle to the sublime tubercle and extends distally along the ulnar ridge. The reported average length of AB is between 21.1 mm and 31.4 mm (2,9,10,17,20,23). These lengths were measured from the origin's center to the sublime tubercle's center, based on a direct insertion onto the sublime tubercle without a distal extension. In contrast, more recent reports measured the length from the center of the humeral origin to the most distal point of tapered insertion. They reported mean lengths of 53.9 mm (21) and 51.7 mm (22). The difference in length measured between a non-tapered sublime insertion and a tapered insertion calls for further study to evaluate native AB anatomy. The appropriate length of the ligament component has important implications for ligament reconstruction.

It is important to remember that the AB is not an isometric soft tissue stabilizer. It changes in length throughout flexion. The length of AB changes by 18%, between 2.8 mm and 4.8 mm as the elbow moves from extension to flexion (6,10,24). The dynamic length of the AB must also be kept in mind during reconstruction procedures.

Width: The width of the AB varies. It increases distally to its greatest width at the sublime tubercle before tapering to a point as it inserts distally along the ulnar ridge. Generally, there has been limited variability in widths of the AB, ranging from 4.0 to 7.6 mm (2,5,10,17,25,26).

Surface area: The reported mean surface area of the AB is between 108 mm2 to 135 mm2 (2,10) in studies that did not consider the full distal footprint. Given that Dugas et al (19) have shown the tapered ulnar footprint alone to have a mean surface area of 127.8 mm2, the overall surface area of the ligament will undoubtedly be significantly greater than previously assumed. A more recent study published by Camp et al (18) has shown the mean surface area of the entire AB to be 324.2 mm2.

Biomechanics

Valgus instability

When a valgus stress is applied the MUCL provides a vital contribution to the stability of the elbow. Morrey and An in a fresh frozen cadaveric model showed that with an intact radial head, the MUCL contributes 31% and 54% to valgus restraint at 0° and 90° of flexion, respectively (1). In this study,  varying valgus loads from 0 to 3 nm were applied at 0° and 90° of flexion in 4 fresh frozen cadavers. There was 3° of valgus laxity in full extension and 2° of laxity in flexion with the maximum force applied. There are several studies that have performed similar biomechanical testing at various degrees of flexion and various amounts of force (2,3,5,6,10,25,27). The amount of valgus laxity varies from 2° to 8° when the MUCL is intact.

Callaway et al (3) showed valgus laxity of 3.6° under a 2nm load compared to an unloaded elbow at 30° and 90° of flexion. Safran et al (5) studied 12 cadaveric specimens with a 2Nm load applied at 30 degrees of elbow flexion, and showed a mean alignment of 10.7° of valgus with a neutral forearm rotation. This study did not determine the inherent valgus alignment in an unloaded elbow. Hence it is not possible to compare these studies. With an intact MUCL and a 2 nm load applied, the amount of valgus laxity is generally greatest at 30° of flexion (5).

The effect of transecting the AB on elbow stability has been studied by several authors. In cadaveric models when the AB is disrupted, the amount of valgus instability increases until the point at which secondary osseous stabilizers such as the radial head provide stability. Callaway et al (3) demonstrated the greatest instability at 90° of flexion in the presence of AB deficiency. The study reported a gain of 1.6, 2.8, 3.2, and 3.0 degrees of valgus motion at 30, 60, 90, and 120 degrees of flexion, respectively compared to the intact state. Mullen et al (28) showed that at 90 degrees of flexion, AB transection increases valgus instability by 150%. Floris et al (25) and Søjbjerg et al (29) showed that the greatest instability occurs at 70 degrees of flexion, with recorded valgus angles of 11.8˚ and 14.2˚. Safran et al (5) produced a maximal gain of 6.3˚of laxity under 2 nm of valgus load with a transected AB at elbow flexion of 50˚. Finally, Morrey et al (4) showed a gain of laxity over baseline ranging from 3.3˚ to 4.8˚ in cadaver specimens at 20 degrees of elbow flexion. An intact AB is vital in maintaining valgus stability of the elbow throughout the flexion range.

Rotational instability

Forearm internal rotation is constrained by the soft tissue stabilizer of the medial elbow. While there is inherent internal rotation of the forearm during flexion, the degree of rotation is limited between 2.8˚-6˚ in an uninjured elbow (4,6,25). Transection of the AB allows internal rotation of the forearm to increase to 18.5˚ at 60˚ of joint flexion (25). A correct understanding of these biomechanics is important in repair and reconstruction since rotatory moment is part of the mechanism of injury.

Tissue strength

The AB is the most frequently injured ligament in overhead throwing athletes, although it has been shown to have the most inherent strength and stiffness (6,17). This shows that significant loads are placed on the medial side of the elbow during the late cocking and early acceleration phase (30,31). In a cadaveric model when each soft tissue stabilizer was evaluated under stress, the AB was found to be the strongest with an average load to failure of 260.9 N (17). During overhead throwing, the elbow experiences 64nm of mean valgus torque and 290N of tensile force on the medial side which is greater than the threshold for failure of 260.9N (30,31). A maximal mean valgus load of 90Nm has been reported (32-34). In a recent study of 81 professional baseball pitchers (MLB and MiLB), over 82000 throws showed a mean valgus torque of 60 nm with individual participant means ranging from 41 nm to 94 nm (35). Hence, it is evident why the AB fails in this subset of athletes based on the load to failure being below the force imparted on the elbow.

Conclusion

The AB of the medial ulnar collateral ligament complex plays a crucial role in elbow stability, especially as a valgus and rotational constraint. The AB originates on the humerus. It inserts onto the sublime tubercle of the ulna. Based on recent studies, the ulnar footprint has a broader insertion that is more tapered and elongated than previously thought. The data regarding the centers of the ulnar and humeral footprints guides proper tunnel placement during reconstructive procedures. 

Although the ligament is quite strong, the amount of force placed across the elbow in elite overhead-throwing athletes routinely exceeds the ligament's average load to failure. Hence it is not surprising why MUCL injuries are so common amongst baseball players and pitchers.

Understanding the native anatomy and biomechanics of the MUCL is clinically important to help understand the pathoanatomy and also to guide surgical techniques when treating MUCL injuries.

References

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4. Morrey BF, Tanaka S, An KN. Valgus stability of the elbow. A definition of primary and secondary constraints. Clin Orthop Relat Res. 1991;265:187–195. 

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24. Armstrong AD, Ferreira LM, Dunning CE, Johnson JA, King GJ. The medial collateral ligament of the elbow is not isometric: an in vitro biomechanical study. Am J Sports Med. 2004;32:85–90. doi: 10.1177/0363546503258886.

25. Floris S, Olsen BS, Dalstra M, Søjbjerg JO, Sneppen O. The medial collateral ligament of the elbow joint: anatomy and kinematics. J Shoulder Elbow Surg. 1998;7:345–351. doi: 10.1016/s1058-2746(98)90021-0.

26. Timmerman LA, Andrews JR. Histology and arthroscopic anatomy of the ulnar collateral ligament of the elbow. Am J Sports Med. 1994;22:667–673. doi: 10.1177/036354659402200515. 

27. Rooker JC, Smith JRA, Amirfeyz R. Anatomy, surgical approaches and biomechanics of the elbow. Orthop Trauma. 2016;30:283–290.

28. Mullen DJ, Goradia VK, Parks BG, Matthews LS. A biomechanical study of stability of the elbow to valgus stress before and after reconstruction of the medial collateral ligament. J Shoulder Elbow Surg. 2002;11:259–264. doi: 10.1067/mse.2002.122622. [DOI] 

29. Søjbjerg JO, Ovesen J, Nielsen S. Experimental elbow instability after transection of the medial collateral ligament. Clin Orthop Relat Res. 1987;218:186–190. 

30. 30.Werner SL, Fleisig GS, Dillman CJ, Andrews JR. Biomechanics of the elbow during baseball pitching. J Orthop Sports Phys Ther. 1993;17:274–278. doi: 10.2519/jospt.1993.17.6.274. [DOI] 

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32. Fleisig GS, Kingsley DS, Loftice JW, Dinnen KP, Ranganathan R, Dun S, Escamilla RF, Andrews JR. Kinetic comparison among the fastball, curveball, change-up, and slider in collegiate baseball pitchers. Am J Sports Med. 2006;34:423–430. doi: 10.1177/0363546505280431. 

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35. Camp CL, Tubbs TG, Fleisig GS, Dines JS, Dines DM, Altchek DW, Dowling B. The Relationship of Throwing Arm Mechanics and Elbow Varus Torque: Within-Subject Variation for Professional Baseball Pitchers Across 82,000 Throws. Am J Sports Med. 2017;45:3030–3035. doi: 10.1177/0363546517719047.