sheldon - hall syndrome ( shs , mim # 601680 ) , or distal arthrogryposis ( da ) type 2b , is a rare autosomal dominant , inherited arthrogryposis syndrome characterized by congenital contractures of two or more different body areas , with no primary neurological disease .
the common clinical features of shs include contractures of the distal limb joints causing camptodactyly , and clubfeet , triangular face , downslanting palpebral fissures , prominent nasolabial folds , small mouth , and high arched palate ( 1 ) .
shs is distinguished as a separate entity from freeman - sheldon syndrome ( fss , da type 2a , mim # 193700 ) , another da type 2 syndrome , because fss includes striking contractures of the orofacial muscles and is a more severe da than shs ( 2 ) .
da is a genetically heterogeneous disorder , with at least 10 different da types characterized to date ( 3 ) .
although the prevalence of arthrogryposis is known to be 1/3,000 ( 4 ) , there are no epidemiological data for da and fewer than 100 cases of shs have been reported in the literature ( 5 ) . to date , five genes that encode the skeletal muscle contractile fiber complex have been confirmed as the causative genes of da types 1 and 2 . among these
, mutations in tnni2 , tnnt3 , tpm2 , and myh3 have been shown to cause shs ( 6 ) . in this study , we present for the first time a korean family with two generations of shs , resulting from a rare tpm2 mutation , who manifested the facial features , short stature , and da typical of shs .
we studied a family in which shs affected two individuals , a mother and her daughter .
a one - month - old korean girl was referred to the seoul national university children 's hospital , for the evaluation of multiple congenital contractures of both hands and feet on december 22th , 2011 .
the patient was delivered by cesarean section , because of her mother 's narrow pelvic bones , at the 38th week of gestation ; her birth weight was 2.56 kg ( 3rd-10th percentile ) and her birth length was 43.0 cm ( < 3rd percentile ) . on prenatal ultrasonography , bilateral clenched hands and bilateral talipes equinovarus were suspected . at the initial examination after birth , camptodactyly , overlapping fingers , and adducted thumbs
were identified in both her hands . a calcaneovalgus deformity with congenital vertical talus in the right foot and an equinovarus deformity in the left foot
she also displayed subtle facial dysmorphism , including a triangular face , downslanting palpebral fissures , and a small mouth .
ten days after discharge from the neonatal unit of our hospital , the infant was admitted to a regional hospital for pneumonia , presumed to be aspiration pneumonia , for one week . at the age of one month ,
she was on frequent bottle feeding with small amounts of whole milk , because her micrognathia and small mouth caused feeding difficulties .
one month later , she suddenly showed difficulty breathing one hour after feeding at home and was transferred to the emergency room of a regional hospital .
although cardiopulmonary resuscitation was applied on arrival at the emergency room , she did not recover and died .
she was born in the 34th week of gestation with a birth weight of 1.8 kg ( 25th-50th percentile ) .
she had difficulty breast - feeding because of her retrognathia and small mouth , so she was bottle fed .
her height was 153 cm ( 5th-10th percentile ) and her weight was 53 kg ( 25th-50th percentile ) .
her facial characteristics include a triangular face with downslanting palpebral fissures , low set ears with attached earlobes , small mouth , high arched palate , receding chin , prominent nasolabial folds , broad and long nasal bridge and root , and long philtrum ( fig .
she was of normal intelligence , but mild bilateral sensorineural hearing impairment was detected with pure - tone audiometry .
this was accompanied by camptodactyly with ulnar deviation of all 10 fingers on both hands , and bilateral talocalcaneal coalition , with left foot clubbing .
contracture release operations of fingers had been performed five times , and the talocalcaneal coalition had been excised .
however , she did not complain of gait disturbance and the motion in neither hip joint was limited .
familial shs was suspected based on the family 's medical history and the findings and the findings of physical examinations . a direct sequencing analysis of the myh3 , tnni2 , tnnt3 , and tpm2 genes
was performed to confirm shs at the molecular genetic level . a previously reported mutation in exon 4 of the tpm2 gene , c.397c > t ( p.r133w ) , was detected in the daughter ( fig .
a genetic analysis of her parents revealed that the mother carried the same mutant allele .
the tpm2 gene is also known to be one of the causative genes of nemaline myopathy .
therefore , we examined the mother with electromyography ( emg ) , although there was no subjective muscle weakness in her daily activities .
the emg findings revealed generalized myopathy , with relative sparing of the slow - twitch muscle fibers .
we provided genetic counseling for the family , and the mother is planning a prenatal genetic diagnosis in her next pregnancy .
da is clinically defined as a group of inherited limb malformation syndromes , with contractures primarily involving the distal limbs , and skeletal muscle weakness ( 7 ) .
da shows marked clinical and genetic heterogeneity , with at least 10 different forms of da documented to date ( 3 ) , the classification of the different types of da syndromes is difficult because of the reduced penetrance and variable expression of the disease .
fss and shs are the most distinctive da subtypes because they include additional facial characteristics .
recently , mutations in the genes encoding the skeletal muscle contractile fiber complex ( tnni2 , tnnt3 , tpm2 , myh3 , and mybpc1 ) have been identified as the causes of da types 1 and 2 ( 6 ) . among these genes ,
mutated myh3 is thought to be the most common cause of shs , with myh3 mutations found to account for 32% of shs ( 8) .
therefore , we sequenced the tnni2 , tnnt3 , and tpm2 genes directly and identified the p.r133w mutation in tpm2 .
tropomyosin is central to the control of calcium - regulated striated muscle contractions via its interaction with actin and the troponin complex ( 9 ) .
tropomyosin has three isoforms ,  ,  , and -tropomyosins , and -tropomyosin is encoded by the tpm2 gene .
tpm2 is mainly expressed in slow - twitch muscle fibers , but -tropomyosin protein expression is higher in fast - twitch muscle fibers than in slow - twitch fibers ( 10 ) .
different tpm2 mutations have been identified in association with a wide range of skeletal myopathies besides das , including congenital myopathy , nemaline myopathy , and cap disease ( 11 , 12 ) .
however , das associated with tpm2 mutations are quite rare : only two tpm2 mutations have been reported as causes of da , each in only one family .
the p.r91 g mutation was found in one family with da type 1 ( 13 ) , and the p.r133w was identified in one family with shs with muscle weakness . however , the muscle weakness associated with this mutation was not accompanied by progressive muscle wasting or histopathological abnormalities , except slow - twitch fiber predominance ( 14 ) . although we did not take a muscle biopsy and our patient did not complain of motor weakness during her daily activities , her emg results suggested generalized myopathy , with relative sparing of slow - twitch muscle fibers .
the previously reported patients with the p.r133w mutation were 28 and 65 yr old at the time , and had prominent muscle weakness , mainly in the hands and feet .
mild progression of this muscle weakness was described only by the 65-yr - old patient .
our patient is 26 yr old now , and further long - term follow - up with regular monitoring of her motor function will be necessary .
the mechanism by which certain mutations in tpm2 cause multiple congenital contractures is still unclear .
one hypothesis is that mutations in the tropomyosin genes cause changes in the actin - myosin interaction and modify the contractile speed ( 11 ) .
a previous in vitro study of the p.r133w mutant tropomyosin also showed that this mutation caused a slower actin - myosin attachment rate and a faster detachment rate ( 15 , 16 ) .
hence , this mutant protein may cause a reduction in the number of myosin molecules in the strong actin - binding state , resulting in overall muscle weakness and da ( 15 , 17 ) . here , we have reported a family with shs resulting from a tpm2 mutation , who showed typical clinical phenotypes . although shs is a rare disease , it can be transmitted as an autosomal dominant condition and familial recurrence has been reported for approximately 50% of cases ( 18 ) .
progressive motor weakness is also possible , and associated feeding problems may lead to a sudden deterioration of the clinical condition , as in our infant patient .
an accurate diagnosis followed by appropriate management and genetic counseling should be provided to these patients .
 sheldon - hall syndrome ( shs ) is a rare autosomal dominant , inherited arthrogryposis syndrome characterized by multiple congenital contractures of the distal limbs . to date , four genes that encode the skeletal muscle fiber complex have been confirmed as the causative genes . 
 mutations in myh3 have been identified most frequently and few cases of shs caused by tpm2 mutations have been reported worldwide . 
 this report describes , for the first time , a korean family with two generations of shs resulting from a rare tpm2 mutation , p.r133w . 
 the affected mother and daughter manifested typical facial features of shs including a triangular face with downslanting palpebral fissures , small mouth , high arched palate , and prominent nasolabial folds , and showed camptodactyly of fingers and deformities of feet with congenital vertical tali . 
 generalized myopathy with relative sparing of the slow - twitch muscle fibers was also revealed by electromyography in the affected mother . 