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a Pediatrics
c Human Genetics, University of Utah, Salt Lake City, Utah
b Shriners Hospitals for Children, Intermountain Unit, Salt Lake City, Utah
d Freeman-Sheldon Parent Support Group, Salt Lake City, Utah
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS. Data from questionnaires, medical charts, examination, and photographs were analyzed to describe the physical features, therapeutic interventions, and functional outcomes in 73 individuals referred with the diagnosis of FSS.
RESULTS. Only 32 referred cases (
40%) met diagnostic criteria for FSS. In addition to contractures, common features in these cases included severe scoliosis (85%), strabismus (42%), and hearing loss (30%). Most infants required supplementary feedings via a nasogastric (45%) or gastrostomy tube (17%). Children walked by an average age of 19 months, but 80% required ambulation-assist devices. An average of 10 surgeries was performed on each child, and anesthetic and/or surgical complications were reported in 50% of individuals. All individuals were cognitively normal.
CONCLUSIONS. The clinical characteristics and natural history of FSS distinguish it from other forms of arthrogryposis, yet FSS is frequently misdiagnosed. Children with FSS require considerable nutritional, surgical, and rehabilitative intervention. Such intensive therapeutic demands differ substantially from most other congenital contracture syndromes. These findings underscore the necessity of making an accurate diagnosis.
Key Words: Freeman-Sheldon syndrome • arthrogryposis • birth defect • myopathy • natural history
Abbreviations: MCC—multiple congenital contracture • DA—distal arthrogryposis • FSS—Freeman-Sheldon syndrome • SHS—Sheldon-Hall syndrome • MH—malignant hyperthermia
Congenital contractures in children can crudely be divided into 2 categories: isolated congenital contractures (eg, clubfoot) and multiple congenital contractures (MCCs). Approximately 1 in 3000 children are born with MCCs, and whereas these cases are usually sporadic, children with MCCs are frequently found to have an underlying syndrome diagnosis, often a disorder inherited in a Mendelian pattern. Accordingly, autosomal-dominant, autosomal-recessive, and X-linked transmission of MCCs is well-documented in multiple kindreds.1–4 Children with MCCs are frequently labeled with the diagnosis "arthrogryposis," defined as nonprogressive congenital contractures of 
2 different body areas. This diagnosis does not imply that etiology or pathogenesis is similar in all children affected with MCCs, because >100 different etiologies for arthrogryposis have been identified.5 Moreover, arthrogryposis syndromes with different etiologies are often associated with widely contrasting natural histories. Distinguishing among these disorders facilitates clinical management, directs anticipatory guidance, and increases the accuracy of recurrence risk estimates.
In the mid-1990s we revised the classification by Hall et al3 of the most common Mendelian-inherited arthrogryposis syndromes, the so-called distal arthrogryposes (DAs).2 Features shared among the DAs include a consistent pattern of distal joint (ie, hands and feet) involvement, limited proximal joint involvement, autosomal-dominant inheritance, reduced penetrance, and variable expressivity. DA syndromes were classified into 10 hierarchically related disorders (ie, DA1–DA10) according to the proportion of features they shared with one another (ie, DA1 is more similar to DA2 than it is to DA3, and so on). This classification has been useful and important for increasing the accuracy of diagnoses and improving patient management. It was also a prerequisite to identifying the genetic basis of DA syndromes and, in turn, providing information about the molecular mechanisms influencing contractures in general.6,7
The prototypic DA is called distal arthrogryposis type 1 (DA1). DA1 is characterized by contractures of the distal joints of the hands and feet, usually camptodactyly and clubfoot, respectively, without involvement of the facial muscles or other organ systems. Proximal joints (eg, shoulders and hips) are sometimes affected, but this finding is less common. Among the DAs, the phenotype of DA1 is most similar to a disorder called Freeman-Sheldon syndrome (FSS).8 Hence, FSS was called DA2.
FSS is a rare MCC syndrome that is nonetheless relatively well-known because affected children often have, in addition to contractures of the limbs (Fig 1), striking contractures of the facial muscles. These contractures result in a very small oral orifice, often only a few millimeters in diameter at birth (Fig 2), so FSS is also known as "whistling-face syndrome."9 Additional facial characteristics include down-slanting palpebral fissures, prominent nasolabial folds, hypoplastic alae nasi, a long philtrum, "pinched" lips, a small mouth, and "H-shaped" dimpling of the chin.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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A referral diagnosis of FSS made by a clinical geneticist was required for inclusion (ie, ascertained cases who were not diagnosed with FSS by a clinical geneticist were not included). Subsequently, phenotypic data and photographs were reviewed by 2 pediatric clinical geneticists (M.J.B. and J.C.C.) to determine if referred cases met the diagnostic criteria for classical FSS. The diagnostic criteria included the presence of 2 of the major clinical manifestations of DA plus the presence of a small pinched mouth, prominent nasolabial folds, and H-shaped dimpling of the chin.2,4 Major manifestations of DA included ulnar deviation of the wrists and fingers; camptodactyly, hypoplastic, and/or absent flexion creases, and/or overriding fingers at birth; talipes equinovarus; and calcaneovalgus deformities, a vertical talus, and/or metatarsus varus. Cases not meeting the diagnostic criteria for classical FSS were excluded from the analysis.
Diagnostic criteria for SHS included 2 of the major clinical manifestations of DA plus deep nasolabial folds, a small oral opening, webbing of the neck, and a small but protuberant chin. In contrast to individuals with classical FSS, patients with DA2B have a larger oral opening and lack an H-shaped dimpling of the chin.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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40%) met the diagnostic criteria for classical FSS. Of the other 41 cases, the diagnoses included DA2B (n = 38), multiple pterygium syndrome (n =1), or unknown (n = 2). No photographs were available for 4 of the 32 cases meeting the diagnostic criteria for classical FSS. Accordingly, these 4 cases were excluded from additional analysis, although, in retrospect, the natural history and outcomes were virtually identical to the cases that were included. Infrequently, clinical data on 1 characteristics was missing for a case. In such circumstances, the analysis was based on only the cases for which data were available. In 4 instances, the parent of the proband was also affected with classical FSS, the mother in 3 cases and the father in the remaining case (Fig 4). In 26 cases, the parents were unrelated, in 1 case the relationship was consanguineous (first cousins), and in 1 case the patient was adopted and the family history was unknown. The male/female ratio was 13:15. The average age at which a questionnaire was completed was 14.7 years (median: 7 years; range: 2 months to 62 years).
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1 year; 6 were 2 years; 13 were 6 years; 17 were 10 years). Most individuals (23 of 24) with classical FSS were born at term. One individual was born preterm at 28 weeks estimated gestational age. Decreased fetal movement was reported in 53% (9 of 17), polyhydramnios in 29% (5 of 17), and oligohydramnios in 12% (2 of 17) of pregnancies. No other complications of pregnancy were reported. Average birth weight was 3058 g (median: 3005 g; range: 1120–4018 g; n = 23). Only 1 individual had a birth weight 3rd centile, and only 1 individual had a birth weight >75th centile after adjusting for gestational age, but 35% (8 of 23) had a birth weight 10th centile (median centile: 25th). Average birth length was 47.3 cm (median: 47 cm; range: 37–54 cm; n = 19). After adjusting for gestational age, 11% (2 of 19) had a birth length <3rd centile, and 58% (11 of 19) had a birth length 10th centile. This figure may be biased toward lower percentiles, because an accurate estimate of birth length is difficult to make in the presence of lower-limb contractures. No individual of childhood or adult age had a stature >25th centile (13 of 22 had a stature <5th centile) or a weight >50th centile (13 of 22 had a weight <5th centile). According to the diagnostic criteria for FSS, all but 1 case of classical FSS had congenital contractures of the hands/fingers and ankles/feet/toes (Table 1). A single individual had only hypoplastic flexion creases of the hands and bilateral clubfoot and, thus, met the diagnostic criteria for classical FSS. Twenty-seven individuals had proximal joint involvement with the hips (58%) and elbows (44%) most frequently affected. Additionally, a limited range of motion of the neck was found in 89% of FSS cases. These observations suggest that involvement of the proximal joints is more common in FSS than in SHS or DA1. However, because the proximal joints can be affected in SHS and DA1, these findings alone cannot be used to distinguish among these disorders. On the other hand, 85% of FSS cases reported having scoliosis, often severe and requiring aggressive medical and/or surgical intervention. Scoliosis is uncommon in SHS and DA1. Other common findings in FSS cases included dental crowding, strabismus, and hearing loss (Table 2).
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Development
Cognition was normal in all of the affected individuals, but modest motor delays were reported in all of the cases. The average ages at which motor milestones were achieved were: head control, 4.9 months (median: 5 months; range: 2–9 months; n = 14); rolling over, 6.5 months (median: 6 months; range: 3–12 months; n = 15); sitting without support, 8.9 months (median: 8 months; range: 6–13 months; n = 13); pulling to a stand, 15.3 months (median: 12 months; range: 9–36 months; n = 9); and walking, 18.6 months (median: 16 months; range: 10–48 months; n = 17). The majority of individuals (83%, n = 18) used ambulatory assist devices. Only braces or splints were used in 10 (77%) of 13 cases, whereas 3 (23%) of 13 individuals used a combination of braces/splints plus a walker. One individual used a walker only, and 1 individual used a walker and motorized wheelchair.
Speech delay was reported in 12 (50%) of 24 cases. The average age at which a single word was pronounced clearly was 13.8 months (median: 12 months; range: 8–24 months; n = 11), and the average age for pronunciation of an understandable sentence was 30.6 months (median: 22 months; range: 11–60 months; n = 8). Problems with articulation were reported in 10 (56%) of 18 cases, and an even higher percentage of cases, 12 (67%) of 18, reported a nasal quality to the sound of their speech. The majority of individuals reported that speech therapy was beneficial. No individuals reported developmental regression.
Hospitalizations and Surgeries
The mean number of hospitalizations was 17 per individual (n = 12; median: 7.5; range: 2–70), and the average number of surgeries was 10.3 per individual (n = 24; median: 5.5; range: 0–49). The range of hospitalizations and surgeries per individual is wide. Moreover, some individuals reported that they were scheduled to have additional surgeries in the near future. The frequency of surgeries per anatomical area showed that the majority of surgical procedures were performed on the limbs, including an average of 2.7 surgeries on the lower limbs and 2.2 on the upper limb. Surgical correction of scoliosis was performed in 9 (39%) of 23 cases. Pressure equalizer tubes were placed in 26% of individuals. Approximately half of all individuals (12 of 25 [48%]) required a commissurotomy.
Complications with anesthesia and/or surgery were reported in 10 of 19 individuals: 9 individuals did not undergo surgery or did not respond. The most common complication was difficulty with intubation in 4 cases because of the small size of the mouth and an inability to open the jaw completely. Malignant hyperthermia (MH) was reported in 3 patients. Of these 3, 1 experienced MH and muscle rigidity after the administration of halothane, whereas another individual experienced rigidity of the masseter muscles and MH during the administration of halothane and succinylcholine. Pyrexia without MH was reported in 2 individuals. Thus, pyrexia or MH was experienced by 5 (26%) of 19 individuals with classical FSS.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The first FSS case described by Freeman and Sheldon8 had pinched lips, a small mouth, prominent nasolabial folds, and H-shaped dimpling of the chin. These characteristics have previously been considered pathognomonic for FSS. Most of the cases referred to us with the tentative diagnosis of FSS had a small mouth, but the lips were not pinched. However, absence of pinched lips does not exclude the diagnosis, because the shape of the lips and mouth and the size of the oral orifice changes considerably over time, even in the absence of surgical intervention (Fig 5). Nevertheless, even as adults, dimpling of the lips is observed in most individuals with FSS, whereas it is absent in most individuals with other DA syndromes. H-shaped dimpling of the chin and lips is, nonetheless, not diagnostic of FSS, because 2 individuals referred to us had these findings but lacked contractures of the hands and feet (Fig 6). Alternatively, the expressivity of FSS may be so variable that some affected individuals manifest only contractures of the face. Identification of the genetic basis of FSS may help to resolve this issue.
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Most children with FSS were hospitalized for an extended period of time after birth, because microstomia and oral contractures hindered feeding to the extent that supplemental feeding techniques were required. Supplemental feedings were typically provided with a modified nipple with a widened opening. Nasogastric feedings facilitated transitioning children to independent oral feedings. Several individuals benefited from placement of a temporary gastrostomy tube until widening of the oral commissure was performed. Surgical widening of the oral commissure was, however, not uniformly necessary or always successful (ie, it did not improve oral function). Development of an individualized plan to manage feeding difficulties was facilitated by early evaluation by an occupational/speech therapist and a craniofacial surgeon.
Dental crowding was a universal finding in this cohort of FSS cases. Several individuals required extraction of multiple teeth because of crowding and/or treatment for malocclusion. The presence of microstomia further exacerbated dental care, because access to the oral cavity for routine hygiene and treatment procedures was more difficult.
The musculoskeletal defects observed in individuals with FSS delayed gross motor development and variably compromised normal function of the hands and feet. However, the use of assist devices, particularly for ambulation, substantially improved functional outcomes. Surgical palliation of hand and foot contractures was generally performed on all of the children with classical FSS. The success of surgical intervention was difficult to assess because of the wide range in the number and nature of surgical procedures performed on each individual, partly as a consequence of the varied severity of congenital contractures among FSS cases. At the most extreme, 3 individuals underwent lower-limb amputations because their clubfeet were recalcitrant to surgical correction.
Nearly 90% of children with classical FSS developed scoliosis that was progressive and frequently severe. Scoliosis most often was noted in early childhood. Accordingly, the only FSS cases in which scoliosis was not found were 2 months, 9 months, 10 months, and 7 years of age, so these children remain at risk for developing scoliosis. In most cases (ie, 64%), treatment of scoliosis required surgical intervention. In 1 case, the scoliosis markedly worsened after beginning treatment with growth hormone. This observation should be kept in mind if growth hormone is used to increase stature in children with FSS. Long-term prospective studies are needed to better determine the natural history of scoliosis in FSS individuals, but our results suggest that close monitoring and an early, aggressive approach to the treatment of scoliosis should be considered.
A variety of abnormalities were observed at a modest frequency in children with FSS. Strabismus was observed in 50% of cases, and because the strabismus is likely caused by an intrinsic muscle abnormality, it is probably reasonable to lower the threshold for surgical palliation. The known genetic etiologies of DA syndromes involve abnormalities of the contractile apparatus of fast-twitch myofibers. Therefore, the observation that individuals with FSS frequently have strabismus might be a clue to the etiology of FSS in this subset of patients, because the external ocular muscles are rich in fast-twitch myofibers. Cryptorchidism (42%) and hernias (23%) will also require surgical evaluation. In addition, hearing loss was noted in 30% of cases (n = 27), and 26% of children with FSS had pressure equalizer tubes placed because of recurrent otitis media.
Nearly every individual with FSS required multiple surgical procedures, and anesthetic complications were relatively common. It is, therefore, important to consider anesthetic risks carefully before surgery and to have in place an appropriate plan to manage complications if they arise. Three FSS cases in our cohort developed MH. MH and muscle rigidity after anesthesia has been reported previously in 3 children with FSS,12,13 although 2 of these cases were included herein. Nevertheless, the number of MH cases in our cohort is probably conservative, because "nontriggering" agents were frequently used on FSS cases undergoing surgical procedures after the publication of these reports in the early 1990s. Although MH-triggering agents have clearly been used successfully in individuals with FSS, it seems prudent to avoid such agents when possible in FSS. The observation that MH is more frequent in FSS underscores the possibility that FSS might be an unconventional myopathy with an etiology similar to other DA syndromes.
Tracheal intubation is difficult in individuals with FSS because of the small mouth. Laryngoscopy-assisted intubation has been used successfully after inhalational induction under deep anesthesia without the use of neuromuscular blocking agents.14 In addition, a laryngeal mask airway and nontriggering anesthetic technique has been used and could be beneficial for short procedures.15 Some patients with FSS also developed postoperative respiratory distress necessitating a prolonged hospitalization with ventilatory support. Overall, because of these anesthetic risks, children with FSS should preferably undergo surgical procedures requiring general anesthesia only at tertiary care institutions, preferably those with a pediatric intensive care unit.
Cognition was normal in all of the FSS cases, but each of them experienced speech and motor delays in childhood. These delays were likely attributable in large part to the physical constraints imposed by the contractures. Indeed, each of the individuals in this cohort substantially improved with a combination of physical therapy, splinting, and surgery.
Based on the natural history and clinical findings observed in this cohort of FSS cases, we make the following recommendations for initial evaluation and anticipatory guidance. At birth, a child suspected of having FSS should, in addition to their primary care provider, be evaluated by several specialists including: a clinical geneticist, an orthopedic surgeon, a craniofacial surgeon, a speech/occupational therapist, and a physical therapist. On physical examination, particular attention should be paid to the size of the mouth; the presence of contractures of the face, hands, and feet; and the presence of strabismus, scoliosis, inguinal hernias, and cryptorchidism. A hearing screen should be performed. In infancy, growth parameters should be monitored closely and the need for supplementary feedings by ancillary mechanisms assessed regularly. Annual examinations should include a hearing test and close inspection for the presence of scoliosis. Presurgical evaluation should include an assessment of risk for malignant hyperthermia.
Most cases of FSS are sporadic, although evidence of autosomal-dominant transmission for FSS is clear. Yet, previous reports of FSS in affected siblings of unaffected parents have suggested that FSS can be inherited in autosomal-recessive and X-linked–recessive patterns.16–23 There are 2 likely alternative explanations for these observations. First, some of these reported familial cases likely did not have FSS, although there are few well-documented examples of other DA disorders transmitted in any pattern other than autosomal-dominant either. Second, an autosomal- or X-linked–recessive pattern can also be observed in cases in which a parent has nonpenetrant somatic mosaicism or germ-line mosaicism. Such is the case for at least 2 families with SHS in which affected siblings were found to have mutations in TNNI2, whereas both parents had only wild-type TNNI2 alleles. We hypothesize that both alternatives will eventually be found to explain most, if not all, FSS cases in which transmission deviates from an autosomal-dominant pattern.
Individuals with FSS should be counseled that the recurrence risk for FSS is 50%, whereas the parents of a child with FSS should be counseled that their recurrence risk is probably only slightly higher than the population risk (ie, background). Prenatal diagnosis has frequently been accomplished via ultrasound examination, although contractures in DA disorders are frequently not evident until 18 to 24 weeks of gestation. Additionally, because of the phenotypic similarity among DA1, SHS, and FSS, distinguishing among them in the prenatal period is challenging. Identification of the genetic basis of FSS will facilitate the prenatal diagnosis by making direct testing of DNA from a sample of chorionic villus or amniotic fluid possible.
The overlap of clinical characteristics of FSS with other DA syndromes suggests a shared etiology and/or pathogenesis. Over the past few years, it has been discovered that several DAs can be caused by mutations in 4 genes that encode proteins of the troponin-tropomyosin complex of fast-twitch myofibers. Specifically, mutations in TPM2, TNNI2 or TNNT3, and MYH8 cause DA1, SHS, and trismus-pseudocamptodactyly (ie, DA7), respectively (M.J.B., unpublished data).6,7,24 Several of the cases of SHS in which mutations were found were originally diagnosed with FSS, but none of these cases met our diagnostic criteria for classical FSS. We screened the subset of FSS cases from our cohort for which DNA was available (n = 16) for mutations in TNNI2, TNNT3, and TPM2, but no pathogenic mutations were found. Nevertheless, we hypothesize that FSS is also a disorder of muscle in which none of the conventional signs of a myopathy are present but is caused by mutations in genes that encode proteins of the contractile apparatus of fast-twitch myofibers.
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ACKNOWLEDGMENTS |
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We thank the patients and their families for participation; the Freeman-Sheldon Parents Support Group for their cooperation; Bridget Kramer, Andrea Sowa, and Cameron Dolcourt for technical assistance; and Jack Dolcourt and Judith Hall for discussion.
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FOOTNOTES |
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Address correspondence to Michael Bamshad, MD, Department of Pediatrics, University of Washington, Box 356320, 1959 NE Pacific St, HSB RR349, Seattle, WA 98195. E-mail: mbamshad{at}u.washington.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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  N. D Embleton and K. V S Pillalamarri Whistle blowing in clinical diagnosis Arch. Dis. Child. Ed. Pract., June 1, 2007; 92(3): ep70 - ep75. [Full Text] [PDF]
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