Freeman-Burian syndrome

Disease name and synonyms

Freeman-Burian syndrome (FBS): MIM 193700, ICD-10 Q87.0, ORPHA 2053; Freeman-Sheldon syndrome, craniocarpotarsal dystrophy; craniocarpotarsal dysplasia; whistling face syndrome; distal arthrogryposis type 2A.

Definition

Freeman-Burian syndrome (FBS) is a rare congenital myopathic craniofacial syndrome [1, 2]. Considerable variability in severity is seen, but diagnosis requires the following: 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 essentially all do, typically camptodactyly with ulnar deviation of the hand and talipes equinovarus. Relatively little is known about FBS (Fig. 1). FBS is first described by Freeman and Sheldon (1938) [3], and independent confirmation of a distinct pathological entity is provided by Burian (1963) [4], who coined the memorable ‘whistling face’ descriptor.

Nomenclature

Since its first description [3], the nomenclature of the syndrome has remained problematic, with no less than six synonyms having been asserted [1]. The term Freeman-Burian syndrome has been suggested to replace Freeman-Sheldon syndrome [1]. Among other benefits, the new eponym avoids confusion with the distinct but phenotypically similar Sheldon-Hall syndrome (SHS; MIM 601680) and highlighting the syndrome’s pathognomonic craniofacial features at one stroke by the use of Francis Burian’s surname rather the Joseph Harold Sheldon’s [1, 3, 4].

Neonatal and early childhood health concerns

Respiratory complications are common during the perinatal and neonatal period but are under-reported in the literature. Idiopathic febrile and apnoeic episodes occur sometimes in infancy and early childhood. Developmental delays may be present in a number of areas, secondary to varying degrees of physical limitations (Ritchie SK. Personal communication. 29 July 2005). Infancy may be characterised by failure-to-thrive for many patients with FBS due to associated dysphagia, microstomia, micrognathia, high palate, and microglossia. An initial soft diet and frequent feeding of small volume is typically required. Though not expressly referenced in the literature, many patients present with a thin habitus and small stature in childhood. Inguinal hernia may also be seen [8, 9]. Difficulties encountered in infancy seem to stabilise and improve with age for most patients.

Functional genetics

The most common FBS-associated allelic variations appear to disrupt adenosine triphosphate (ATP) binding to MYH3 and are suggested to influence myophysiology during early development, producing joint contractures due to haploinsufficiency of MYH3’s product and eventual downregulation, retarding muscle development, and leaving residual defects [10, 11]. Muscle cells and myofibrils from patients with FBS show attenuated specific force, lengthened time to relaxation, and higher baseline residual force, caused by presence of fewer myosin cross-bridges and attenuated detachment kinetics [12]. There is also slow and incomplete deactivation of thin filaments during the latter part of contraction [12]. ATP hydrolysis is prolonged five to nine times normal range, delaying subsequent metabolic action [13]. The MYH3 allelic variations Y583S and T178I expressed in Drosophila result in extreme muscular stiffness, causing a 45% reduction in work and 62% in maximal power [14].

Operative findings

In patients with FBS, white fibrous tissue within histologically normal muscle fibres and complete replacement of muscle by fibrous and adipose tissue is observed operatively [1, 15]. In some areas, entire muscles are grossly and histologically normal [1, 15]. There may be variable syndromic affectation in different body regions and possibly down to muscle groups or individual muscles [1, 15]. The areas of fibrous tissue replacement behave like tendinous tissue, which is often released to reduce the contractures [1]. Operative findings in FBS correlate well with in vitro molecular myophysiology observations [1, 12–14]. Blepharophimosis may be precipitated by blepharospasm earlier in development, when muscle in the eyelid is present [15]. This muscle tissue is destroyed—probably at the neuromuscular junction level—causing connective and adipose tissue replacement [15].

Neurogenic syndromes

Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD; MIM 616266) is a distinct autosomal dominant lethal condition distinguished from FBS by profound and progressive neurological motor and cognitive impairment [19]. At least 14 different allelic variations in the pore-forming area (S5 and S6 segments) of the sodium leak channel, non-selective (NALCN; MIM 611549) gene are associated with CLIFAHDD [19]. All patients with CLIFAHDD [20, 21] are suggested to have de novo sporadic heterozygous allelic variations [19]. There may e overlap of CLIFAHDD with Illum syndrome (MIM 208155), lethal whistling face with limb deformities, but both are distinct from FBS.

Sheldon-hall syndrome

Often confused with FBS and once termed Freeman-Sheldon variant, SHS exhibits a similar phenotype as classic FBS, but patients lack severe microstomia and history of dysphagia and display a triangularly shaped face; small, prominent chin; and equinovalgus [16]. In FBS, patients show an elongated face, severe microstomia, micrognathia, and equiniovarus [16]. Generally, SHS is considered less severe than FBS [16]. Inheritance in SHS is autosomal dominant [16]. SHS is associated with allelic variations in the fast skeletal muscle troponin T and I gene (TNNT3 and TNNI2; MIM 600692 and 191,043) [22], tropomyosin beta chain gene (TPM2; MIM 190990) [23], and MYH3 [10]. SHS-associated allelic variations R174Q and R156X on TNNI2 gene and R63H on TNNT3 gene are associated with increased ATPase activity, suggesting increased calcium sensitivity and increased contractility [24].

Other phenotypically similar syndromes

Distal arthrogryposis type 1A (MIM 108120) and distal arthrogryposis type 1B (MIM 614335) strongly resemble the limb malformations of FBS and SHS but lack craniofacial features. Both also demonstrate an autosomal dominant inheritance pattern and are caused by allelic variations of the TMP2 gene. Distal arthrogryposis type 3 or Gordon syndrome (MIM 114300) is considered distal arthrogryposis type 1 with additional features, including: cleft palate, blepharoptosis, and abnormal spinal curvatures, again lacking specific craniofacial findings of either FBS or SHS. Gordon syndrome is associated with allelic variations on the piezo type mechanosensitive ion channel component 2 gene (PIEZO2; MIM 613629) [25]. Arthrogryposis multiplex congenita is a distinct entity from FBS and the conditions collectively known as distal arthrogryposes.

Some phenotypical overlap for FBS also exists with Schwartz-Jampel syndrome (MIM 255800), distal arthrogryposis type 7 or trismus-pseudocamptodactyly syndrome (MIM 158300), and distal arthrogryposis type 8 or multiple pterygium syndrome (MIM 178110). Schwartz-Jampel syndrome is distinguished from FBS by myotonic myopathy, which is not present in FBS, though joint, spine, and eye problems may be similar to FBS. While patients with trismus-pseudocamptodactyly syndrome have limited mouth opening, they lack true microstomia. Pseudo-camptodactyly is also a distinguishing feature not present in FBS, though micrognathia, dysphagia, and a long philtrum occur in FBS and trismus-pseudocamptodactyly. FBS and multiple pterygium syndrome share pterygium of certain joints, though this finding is much more prominent in the latter condition.

Molecular testing

There is no diagnostic or therapeutic benefit of molecular testing for individuals with FBS clinical phenotype. Due to a lack of clinical correlation data on different potentially pathological genotypes, molecular testing cannot confirm diagnosis, unless a previously correlated genotype is found in the individual. While efforts have been made to correlate natural history and diagnosis with specific genotypes [11, 18], this level of detailed information does not exist outside of a couple of genotypes studied; thus, the resulting genotype generally cannot be used, at this point, to individualise therapy. Genetic therapies, in and of themselves, are very distant. Although offered as a clinical test, the utility of molecular testing in individuals with a FBS clinical phenotype is purely from its value as a research tool, and families should not be misled. Reliable and repeatable diagnosis originates from the presence of the pathognomonic group of craniofacial stigmata (whistling face, microstomia, prominent nasolabial folds, and H- or V-shaped chin defect), and results of molecular testing do not, at this time, add useful clinical data.

Anaesthesia

The anaesthetic management of patients with FBS is complicated by orofacial contractures, limited neck mobility, spinal deformities, and difficult vascular access [29]. Though it is suggested that up to 50% of patients with FBS are malignant hyperthermia (MH) susceptible, this is not substantiated by more recent reports [3]. Nevertheless, an MH-safe anaesthetic technique is standard for FBS patients [29]. The published anaesthesia management protocol includes an enumeration of potential challenges and complications in FBS patients [29], a discussion of which is beyond the scope of this review.

Craniofacial surgeries

Oral commissuroplasties for microstomia correction to facilitate oro-tracheal intubation, dental treatment, oral hygiene, speaking, and oral nutrition are the most common surgery overall [30–40]. Repeated myringotomies with pressure equalisation tube placement is discussed [35, 37, 41, 42]. Correction of alar nasi hypoplasia with V-Y advancement flaps is discussed [4, 37]. Modified bilateral therapeutic blepharoplasty with a static sling to the epicranious frontalis for blepharophimosis and blepharoptosis is described, with stable results at 9-year follow-up [15]. Other approaches to blepharophimosis and blepharoptosis are described, including: complete forehead reshaping and use of a static sling to the epicranious frontalis [36], static sling to the frontalis without procedural details [35], and bilateral canthoplasties [43]. Strabismus correction [9, 36], dental extractions [15, 44], dental implant insertion [39], and frenectomy and choanal atresia repair [37] are also reported.

Hand surgery

Multiple authors discuss hand reconstruction [9, 32, 45, 46], which generally does not result in stable long-term results, but therapeutic outcome is likely due more to suboptimal patient compliance with occupational therapy. Most hand procedures include first web-space widening, capsulotomies, and tendon releases and lengthening.

Lower extremity surgeries

Operative correction of lower extremity deformities generally results in unfavourable results [3, 9, 33, 35, 36, 47–52]. McCormick et al. (2015) describe a patient that required multiple full-thickness skin grafting after failed bilateral equinovarus correction, lost functional use of the feet, was confined to a wheelchair for fifteen years, and eventually was fitted with bilateral Symes-type lower extremity prostheses without amputation [53]. Unsuccessful surgical release of knee contractures [48] and open reduction of congenital hip dislocations [48, 51] are also described.

Other surgeries

Correction of spinal deformities is mentioned [54], with one patient requiring HALO traction [48]. Correction of pedal polydactylism [43], ureteric reimplantation [55], aortic valve replacement in a 64-year-old man with multiple non-syndromic cardiovascular comorbidities [56], resection of gangrenous testes [3], and resection of an ovarian cyst and bilateral salpingectomy [9] are also mentioned in the literature.

Non-operative therapy, psychosocial concerns, and longitudinal care

While surgical intervention is inevitable in FBS patients, the Ponseti method is described to correct equinovarus in FBS and distal arthrogryposis syndromes [57]. In FBS and distal arthrogryposis patients, post-therapeutic bracing is usually required to maintain correction beyond the average 4 years of therapy for patients without FBS or distal arthrogryposis (Ponseti IV. Personal communication. 3 January 2007). Two successful 3-month proof-of-concept trials of intensive passive manipulation and bracing for correction of multiple chronic bilateral hand and wrist deformities in an adult female patient with classic FBS is described [58]. Few authors mention psychosocial function in FBS, and none discuss psychiatric care or the impact on families. Poor self-image; feelings of inadequacy, anger, and rage; post-traumatic stress disorder; and depression associated with FBS have been described [34, 42]. In addition to depression and disorders of traumatic aetiology, some patients with FBS develop social anxiety, substance abuse, and maladaptive sexual behaviours. It is also probable that at least some of the gastroenterological problems attributed to physiological aberrations of FBS have a psychosomatic aetiology. Importantly, patients with FBS exhibit greatly reduced facial animation, providing limited non-verbal cues to appraise their affect, a factor that has to be considered when assessing fear, anxiety, and pain in patients with FBS. Overall, long-term management should not focus exclusively on health maintenance but on continual improvement of functional outcomes. This important distinction is often overlooked, resulting in missed opportunities to help patients.

Unresolved questions

While basic science data are now available and add important information, significant gaps in the literature remain. Virtually no studies, outcomes data, discussion of psychiatric and physiological burdens, or critical discussion of therapeutic approaches are available. With data on genotype and phenotype correlations and translational data on functional consequences of observed allelic variations, it is foreseeable that great improvements in clinical care are possible.

Studies are specifically needed to evaluate the unique compound psychiatric burden of craniofacial deformities and limb malformations that impact fine motor function and ambulation. Evaluating the biochemical burden and gross physiological consequences of aberrant ATP functioning in FBS are especially important in developing targeted therapeutic interventions that can compensate for this pathophysiology and eventually to correct it. Research may also be warranted to evaluate a possible relationship of idiopathic hyperpyrexia and stress. Without substantive investigation of functional clinical questions concerning FBS, considerable, wide-scale improvement in the care of these patients is unlikely.