Identification and Recent Approaches for Evaluation and Management of Rehabilitation Concerns for Patients with Freeman–Burian Syndrome: Principles for Global Treatment

Abstract

Freeman–Burian syndrome, formerly Freeman–Sheldon syndrome, is a rare congenital complex myopathic craniofacial syndrome that frequently involves extremity joint deformities, abnormal spinal curvatures, and chest wall mechanical problems that, together with spinal deformities, impair pulmonary function. As part of a clinical practice guideline development, we evaluated 19 rehabilitation-related articles from our formal systematic review, and from these and our experience, we describe rehabilitation considerations. Research in this area has widespread methodologic problems. While many challenges are present, much can be done to afford these patients a good quality of life through careful planning.

Introduction

Freeman–Burian syndrome (FBS; MIM 193700), formerly Freeman–Sheldon syndrome ¹ and often referred to as distal arthrogryposis type 2A, craniocarpotarsal dysplasia or dystrophy, or whistling face syndrome, is a rare congenital myopathic craniofacial syndrome. ² FBS is originally described by Freeman and Sheldon (1938) and independently confirmed as a new entity by Burian (1963). ^{3 4} Diagnosis requires ^{5 6 7} microstomia, whistling-face appearance (pursed lips), H- or V-shaped chin defect, and prominent nasolabial folds ( Fig. 1 ). Some patients do not have limb malformations, but those who do, typically present with camptodactyly with ulnar deviation of the hand and talipes equinovarus ^{5 6 7} ( Figs. 1 and 2 ). Spinal deformities, gastroenterologic problems, and other craniofacial problems are frequent findings. ^{5 8} Considerable clinical variability in severity is observed in FBS patients; some individuals present with minimal malformation, ⁹ while rarely others succumb from severe respiratory complications in infancy. ^{10 11} Inheritance of FBS is autosomal dominant, but most are sporadic. ⁵ Prevalence of FBS is unknown, mostly due to diagnostic uncertainty. There appears to be neither sex nor ethnic preference. Environmental and parental factors are not implicated in pathogenesis.

Fig. 1.

Patient, age 21 ( A ) and 32 ( B, C ) years, with a typical presentation of Freeman–Burian syndrome. The required features of microstomia, whistling-face appearance (pursed lips), H-shaped chin defect, prominent nasolabial folds, bilateral camptodactyly, ulnar deviation, and equinovarus (not visible) were clearly demonstrated. Unsuccessful operative equinovarus correction, at age 6 years, rendered the patient nonambulatory until fitted with prostheses, at age 21 years ( A ). While the patient had undergone commissuroplasties, lower lip revision, chin augmentation, and sling attachment to the epicranius frontalis to ameliorate the blepharoptosis, she gained minimal aesthetic and functional improvement ( B ). Her hands were never treated operatively, and limited nonoperative treatment that was showing improvement was abandoned over nonclinical problems ( C ). Our patient’s case has been described elsewhere, ^{13 40} and this figure has appeared elsewhere. ⁴⁰

Fig. 2.

Feet of same patient, aged 21 years, who demonstrates a typical presentation of Freeman–Burian syndrome with bilateral equinovarus and metatarsus varus showing operative modification and full-thickness skin grafting. This figure has appeared elsewhere. ⁴⁰

FBS can be caused by allelic variations in embryonic myosin heavy chain ( MYH3 ; MIM 160720), all but two of which are predicted to impair adenosine triphosphate (ATP) binding to myosin. ⁶ Those thought to disrupt ATP binding are suggested to influence myophysiology during early development, attenuating muscle development and leaving residual defects of muscle contractures. ^{6 12} In patients with FBS, white fibrous tissue within histologically normal muscle fibers and complete replacement of muscle by fibrous and adipose tissues are observed operatively. ¹³ In some areas, entire muscles are grossly and histologically normal. ¹³ The areas of fibrous tissue replacement behave like tendinous tissue, which is often released to reduce the contractures. These operative findings correlate well with in vitro molecular myophysiology observations that show problems with the metabolic process for contraction and extreme muscle stiffness that reduces muscular work and power. ^{14 15 16}

The following discussion of rehabilitation-related considerations in FBS is provided ahead of a comprehensive clinical practice guideline for FBS. Specific areas covered include:

1. Referral for management of limb deformities and abnormal spinal curvatures.

2. Rehabilitation and neurologic evaluation.

3. Spinal curvatures and cardiopulmonary rehabilitation considerations.

4. Hand and lower extremity deformity management. With respect to joint mobility and overall wellness, patients with FBS often benefit the most functionally from nonoperative interventions.

A comprehensive review of FBS ¹⁷ and discussions on diagnosis, evaluation, craniofacial, ¹⁸ dentofacial and otorhinolaryngology, ¹⁹ and anesthetic ²⁰ management have been published elsewhere. Though most patients are diagnosed at birth or in early childhood, this discussion is relevant to all patients with FBS. While primarily directed toward those involved in rehabilitation care, its broader goal is to assist all who encounter patients with FBS and interact with their families. Management of comorbidities not related to or influenced by FBS is not covered.

Materials and Methods

The protocol for the systematic review upon which this discussion of rehabilitation-related topics is based has been completed as part of the unfunded FBS clinical practice guideline development process, received Institutional Review Board approval from FSRG IRB #1 (UTN: U1111-1172-4670), was registered on PROSPERO (CRD42015024740), and published elsewhere. ²¹ A comprehensive review of FBS is beyond the scope of this discussion. As part of this decade-long effort to clarify the descriptor, ¹ definition, classification, ² and clinical care framework for FBS, broad, ¹⁷ and focused ^{18 19 20} discussions, and a meta-analysis ²² covering FBS have been published. Neither the sponsor (Freeman-Sheldon Research Group, Inc.) nor any institution has had any role in protocol development or associated activities. The protocol, including development of actionable clinical questions, has been prospectively drafted in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols. ²³ All actions described have been executed by the review authors.

Results and Discussion

Our main systematic review on FBS yielded 19 results describing rehabilitation concerns in FBS. ²² Due to the substantial gaps in the literature and general paucity of published data, the discussion is supplemented with our experience.

Unique Problems of FBS

The experience of a complex and incompletely understood craniofacial syndrome, such as FBS, is a significant stressor for patients and families. ²⁴ Adding to this psychosocial burden, most patients with FBS present with multiple, serious orthopaedic problems. The constellation of mild to dramatic malformations that can be associated with FBS has no clearly defined defects that are amenable to acceptable aesthetic or functional reconstruction. While there are undoubtedly some similarities between FBS and more common malformation conditions, the muscle tissue in many more common conditions is histologically normal and reacts appropriately to operative repair. The muscle tissue and biochemistry in FBS are atypical, poorly understood, and do not react appropriately to operative intervention. This pathologic difference may herald a worse therapeutic, functional, and occupational outcome for FBS.

Considerations for Referral

Patients with FBS present with multiple rehabilitation considerations, especially mobility impairments associated with lower extremity deformities, manual dexterity impairments associated with multiple hand and wrist contractures, and pulmonary complications related to dysphagia, ineffective intercostal muscles, and abnormal spinal curvatures. To successfully mitigate these problems, comprehensive, long-range rehabilitation planning and management is required. Historically, orthopaedic surgeons have provided rehabilitation planning for these patients, which often focused on serial casting for foot deformities in combination with surgery. Clinical experience and case report evidence suggest that this approach is not optimal and that rehabilitation of limb and spinal deformities requires more comprehensive management better provided by physiatry. Although it may seem axiomatic for physiatry to provide rehabilitation planning and management for a patient population with significant and complex problems, some university-affiliated tertiary care referral centers bar patient access to physiatry consultation. In these situations, patients are referred by their orthopaedic surgeon for rehabilitation only after undergoing operative treatment, a practice both confounding and obstructive to the goal of providing good clinical care.

Rehabilitation Evaluation

Initially, physical examination will determine status and degree of involvement liable to therapeutic intervention versus a possible need for palliation to achieve acceptable functional outcomes. Imaging should be obtained to evaluate the spine (scoliosis, lordosis, kyphosis), feet (equinovarus, metatarsus varus, vertical talus, calcaneus valgus), hips (contractures, dislocations), and knees (contractures, dislocations). Less frequently, shoulders and elbows demonstrate contractures and dislocations. Highly localized syndromic muscles should prompt careful discriminatory analysis of each muscle of clinical importance, beginning with evaluation of skeletal muscle resistance response, joint flexibility, and any associated deformities. When developmentally appropriate, gait analysis and functional evaluations should be a priority. For patients with limited ambulatory function, use of orthotics—essentially hybrid prosthetic devices used on patients who have not undergone amputation—can be useful. In these patients, it is critical to emphasize preprosthetic rehabilitation, which is just as important in patients with congenital foot deformities as for new amputees. Deconditioning is a commonality in both groups. While physiotherapy and occupational therapy should be continued, formal services may not be required for long term. Patients should be frequently re-evaluated for changes in status and degree of involvement liable to surgical improvement or correction.

Neurologic Evaluation

Essentially, all patients will present with some degree of developmental delay and peripheral neurologic abnormalities related to the limited mobility seen in FBS. Joint contractures may limit or prevent evaluation of deep tendon reflexes. Patients with cranial imaging changes related to craniosynostosis must be distinguished from patients with congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD; MIM 616266), a distinct condition from FBS caused by allelic variations in the sodium leak channel, nonselective ( NALCN ). ²⁵ To avoid making inaccurate judgments about the etiology of the developmental delay when evaluating patients, functional testing must be based on what is physically possible for the patient. For example, a common task for young children is placement of small blocks through matching holes. This may be difficult for patients with significant hand deformities or those wearing hand braces, and scoring of this task may lead to an incorrect clinical impression. Rather than score the child on block placement time, a score based on problem solving may be more appropriate.

Spinal Curvatures and Cardiopulmonary Rehabilitation Considerations

For patients with FBS, the potential presence of ineffective intercostal muscles ²⁶ and severe abnormal spinal curvatures can lead to reduced intrathoracic volume, impaired thoracic cage compliance, and restrictive pulmonary disease. Abnormal spinal curvatures may not be responsive to surgical intervention that does not account for the unique muscle problems in FBS and progress, if left untreated. Extreme and refractory spinal curvatures seen in some patients with FBS are also known to impair gastrointestinal function. There is clinical evidence of reduced respiratory effort and impaired tussive effort, thought to be secondary to nonfunctional intercostal muscles and reduced elasticity of the diaphragm. Pulmonary hypertension, right heart strain, and cor pulmonale have been described in FBS, ²⁷ presumably in response to nonfunctional intercostal muscles and chest deformities associated with scoliosis, lordosis, or kyphosis. Bronchitis and pneumonia are frequent complications of both general endotracheal anesthesia and upper respiratory infections in FBS. Unexplained sinus tachycardia without evidence of pathology has also been documented in the syndrome. Cardiology evaluation should include baseline and follow-up 12-lead electrocardiography and recording of right precordial leads, and echocardiogram, though esophageal technique is unlikely to be feasible due to anatomic challenges. Physiologic testing, as developmentally appropriate, should be accomplished and include spirometry, submaximal or maximal ventilation of oxygen (VO _2max ), and resting metabolic rate testing to better understand respiratory efficiency and metabolic needs.

Hand Deformity Management

Most patients present with some degree of pollex adduction, camptodactyly, and ulnar deviation of phalanges and radiocarpal joints ( Fig. 1A , 1C ) and require baseline and follow-up imaging to evaluate the hands, monitor joint development, and detect fibrosis of immobile joints. Multiple authors discuss hand reconstruction, ^{28 29 30 31} which generally does not result in stable long-term results, but these suboptimal outcomes may be due more to poor compliance with or lack of emphasis on physiotherapy and use of braces or splints. Most operative hand procedures included first web-space widening, capsulotomies, and tendon releases and lengthening. McCormick et al (2015) showed that even untreated young adults may be helped with passive physiotherapy and bracing, without need for surgical treatment. ³² Early treatment efforts with infants should be focused on supporting parents to do structured in-home stretching and exercises to increase strength and encourage hand use. Some families have placed small plush animals in children's hands to keep fingers in a more neutral position during sleep. The plush animals are retained in the hands by static tension from the contractures without a need for measures to secure them, avoiding additional sources for possible skin irritation.

When fabricating hand splints in consultation with physiatry, hand surgery, and occupational therapy services, particular attention should be placed on using nonirritating materials and avoiding possible pressure points. Though there is potential for success with delayed nonoperative hand therapy, early correction remains strongly preferred for optimal developmental, social, and physiologic functioning. ³² Experience, however, shows that nonsurgical correction should not be abandoned, even for patients with long-standing or severe hand deformities, provided no skeletal changes in the joints have occurred. ³² To avoid potential assumption of treatment failure by patients, families, therapists, or physicians all must be aware that improvement will be much slower and more difficult in delayed hand therapy. ³²

Lower Extremity Deformity Management

In FBS, lower extremity contractures—manifested as equinovarus, metatarsus varus, and vertical talus ( Fig. 2 )—are associated with poor mobility outcomes when there is not an emphasis on nonsurgical manipulative and rehabilitative interventions. FBS patients with lower extremity contractures who are ambulatory frequently require assistive devices or have some degree of impairment or discomfort ( Fig. 1A ). Operative correction of lower extremity deformities generally results in unfavorable results. ^{3 10 30 33 34 35 36 37 38 39} McCormick et al (2015) described a patient who required full-thickness skin grafting following a failed equinovarus correction and lost functional use of the feet. ⁴⁰ Unsuccessful surgical release of knee contractures ³⁹ and open reduction of congenital hip dislocation ^{33 39} are also described. If indicated, limited surgical intervention is likely to involve tendon and ligament lengthening to support physiotherapy. Ankle and foot procedures, other than mild soft tissue procedures aimed at supporting ongoing physiotherapy goals, are rarely beneficial and frequently harmful.

While surgical intervention is inevitable in FBS patients, the Ponseti method is described to correct equinovarus in FBS and distal arthrogryposis syndromes. ⁴¹ In FBS and distal arthrogryposis patients, post-therapeutic bracing is usually required to maintain correction beyond the average 4 years of therapy for patients that is typical without FBS or distal arthrogryposis (Ponseti IV, personal communication, January 3, 2007).

The goal of lower extremity interventions is to optimize the individual's ability to ambulate and engage in physical activity, not to preserve or reconstruct the patient's biologic feet. This goal can be difficult to envision and accept, but it is critical to acknowledge that the patient's ability to ambulate and be physically active will make a larger contribution to their psychological development, occupational success, and good physical health than anatomic correction of nonfunctional, potentially chronically painful, or marginally functional feet. Patients and parents of young children must understand and accept the therapeutic goal, or all efforts will be lost, even in spite of technical success. Patients and families often believe that the goal is to create anatomically acceptable feet without considering what that may mean functionally or how the clinical outcome will affect occupational and other outcomes.

For treatment-resistant and non- or marginally-functional feet with good vascularization and adequate skin integrity, the foot and limb can be treated successfully as a single stump, though technically much more challenging and requiring greater and more frequent adjustments to the socket than for a stump following amputation. ⁴⁰ The expected need for frequent adjustment over a long duration must be sincerely appreciated by the provider, patient, and family to avoid appearance of therapeutic failure and ensure patient and family compliance. Rapid identification of and corrective measures for skin problems precipitated by friction, sheer, or inappropriate pressure are required. Prostheses without amputation ( Fig. 1A ) can avoid a traumatic surgery, the considerable associated postoperative morbidity, and play a dramatic role in improving the lives of carefully selected patients whose feet could not be functionally improved.

Conclusion

FBS is an extremely rare and highly variable complex craniofacial syndrome that often includes extracraniofacial problems. FBS is often associated with challenging lifelong physical challenges. In most cases reported concerning hand and wrist, ankle and foot, and spinal deformities, suboptimal outcomes result where aggressive, long-term physiotherapy is not the primary therapeutic modality and where operative intervention is central to the treatment plan. While conservative operative intervention holds the possibility for minimizing developmental delay and improving function, the technical ability for improvement is limited in FBS because of the presence of fibrous tissue bands and their tendency to reform. From the absence of reports, VO ₂ and resting metabolic rate testing are underappreciated evaluation modalities that could provide great insights and benefits clinically and from an applied physiology standpoint. Overall, rehabilitative management must be proactive to avoid preventable complications and to physiologically optimize the patient's functional and occupational status. Care should not be reactive maintenance—an important and often overlooked distinction that results in missed opportunities to help patients.

Funding Statement

Funding This article was sponsored by Freeman-Sheldon Research Group, Inc.