catel  manzke syndrome ( mim : 616145 ) is a rare genetic disorder characterized by pierre robin sequence with hyperphalangy and clinodactyly of the index finger , .
affected individuals typically present with the classic features of pierre robin sequence including micrognathia , airway obstruction secondary to displacement of the tongue base , and often , cleft palate .
the orthopedic abnormalities are the result of an accessory bone between the second metacarpal and proximal phalanx that causes radial deviation of the second digit ( manzke dysostosis ) .
cardiac abnormalities , facial dysmorphisms , and additional skeletal abnormalities have also been described in a subset of patients with catel  manzke syndrome , , . until recently , the genetic basis of catel  manzke syndrome was unknown , although inheritance appeared to be autosomal recessive , .
recently implicated homozygous or compound heterozygous pathogenic variants in tgds ( dtdp - d - glucose 4,6-dehydratase ) as the causative factor in a series of seven unrelated patients with features of catel  manzke syndrome . of
the seven unrelated patients reported , c.298 g  >  t ( p.ala100ser ) was the most common pathogenic variant and was hypothesized to be a founder mutation .
tgds encodes a member of the short - chain dehydrogenase / reductase ( sdr ) family ; however the specific function of the protein in humans is unknown . in the present report
, we describe an additional patient with molecularly confirmed catel  manzke syndrome who has pierre robin sequence ( without cleft palate ) and manzke dysostosis , and we compare his phenotype with the phenotype of the seven previously described patients with pathogenic variants in tgds 
 .
he required tracheostomy for severe airway hypotonia with pharyngomalacia and laryngomalacia , and gastrostomy tube placement for failure to thrive likely secondary to his pharyngeal dysphagia and airway obstruction .
the proband was born at 38 4/7  weeks of gestation via spontaneous vaginal delivery without complications to a 29  year - old female .
the mother had a history of three prior first - trimester spontaneous abortions and one healthy son with the same partner .
no prior genetic workup had been performed for the spontaneous abortions , and the cause for these spontaneous abortions was unknown .
his postnatal course was complicated by significant failure to thrive noted as early as three weeks of age . his failure to thrive persisted despite increased caloric density and feeding therapy , and at two months of age ,
a modified barium swallow showed pharyngeal dysphagia , and he was noted to have significant fatigue with feeding .
he was also diagnosed with gastroesophageal reflux . during an admission for failure to thrive , stridor and desaturations to 85%
he was diagnosed with severe pharyngomalacia and laryngomalacia by otolaryngology , and a supraglottoplasty was performed . by six months of age , he was diagnosed with mixed sleep apnea and respiratory insufficiency due to airway hypotonia and oropharyngeal weakness .
these respiratory issues were suspected to contribute to his feeding difficulties and failure to thrive .
tracheostomy was ultimately placed at seven months of age , and he required nocturnal ventilator use .
he also underwent myringotomy and tympanostomy for recurrent ear infections . by eight months of age , a repeat modified barium swallow still showed pharyngeal dysphagia , but his fatigue with oral feedings appeared to be improved .
in addition , by this time , his weight gain slowly began to improve . at his most recent exam at 12  months of age ,
his weight was 8.42  kg ( z score  =    1.22 , who growth chart ) , his length was 72.4  cm ( z score  =    1.36 , who growth chart ) , and his head circumference was 45.9  cm ( z score  =    0.13 , who growth chart ) .
he was using the gastrostomy tube for the majority of his caloric intake but was tolerating small amounts of oral feeds .
he was noted to have prominent overriding sutures , a tubular - appearing nose with high nasal bridge and pinched nares , retrognathia , high and narrow arched palate with small groove of the posterior soft palate , and ankyloglossia ( fig .
his fingers and toes appeared long , and his index fingers were deviated and overlapping . a mild pectus deformity was noted . on hand radiographs
, the second proximal phalanges appeared hypoplastic with an accessory bone located at the base of the second digit , and there was medial deviation of the distal second digits ( fig .
lateral view of the spine demonstrated anterior beaking of the l2 and l3 vertebral bodies .
echocardiogram at three months of age showed a small patent foramen ovale and a small patent ductus arteriosus , both with left to right flow and both of which resolved by six months of age .
routine chromosome analysis , comparative genomic hybridization microarray ( affymetrix cytoscan hd microarray system , scott and white healthcare molecular genetics laboratories ) , very long chain fatty acids ( peroxisomal diseases laboratory , kennedy krieger institute ) , and lysosomal storage panels ( lysosomal diseases testing laboratory , thomas jefferson university ) were also normal .
the proband and both parents were enrolled in our skeletal dysplasia study according to the baylor college of medicine 's institutional review board .
informed consent was obtained specifically for molecular studies and for the publication of clinical information and photographs .
dna was extracted from peripheral blood monocytes and precipitated for polymerase chain reaction and sanger sequencing .
polymerase chain reaction was performed using primers designed to cover the entire coding region of tgds ( supplemental table 1 ) with an annealing temperature of 55  c .
products were verified by agarose gel electrophoresis and then sequenced by chain - termination ( sanger ) sequencing using the same primers at beckman coulter genomics ( danvers , ma ) .
the proband and both parents were enrolled in our skeletal dysplasia study according to the baylor college of medicine 's institutional review board .
informed consent was obtained specifically for molecular studies and for the publication of clinical information and photographs .
dna was extracted from peripheral blood monocytes and precipitated for polymerase chain reaction and sanger sequencing .
polymerase chain reaction was performed using primers designed to cover the entire coding region of tgds ( supplemental table 1 ) with an annealing temperature of 55  c .
products were verified by agarose gel electrophoresis and then sequenced by chain - termination ( sanger ) sequencing using the same primers at beckman coulter genomics ( danvers , ma ) .
sanger sequencing revealed that the proband was apparently homozygous for the c.298 g  >  t ( p.ala100ser ) pathogenic variant , the most common pathogenic variant identified by ehmke et al . .
sanger sequencing of dna samples from the parents revealed that both parents are heterozygous for this variant and thus , confirmed that the patient is homozygous ( fig .
to date , this report is only the second publication describing molecularly confirmed catel  manzke syndrome , and our patient is only the eighth reported patient . we compared our patient 's features with the features of the seven previously reported patients in the original manuscript describing pathogenic variants in tgds as the cause for catel  manzke syndrome ( table 1 ) , , , .
our patient has pierre robin sequence and manzke dysostosis , the two classic features of catel  manzke syndrome . in addition
, he had a minor congenital cardiac defect that resolved and facial features ( narrow nose , full cheeks ) that have been described in a subset of the previously reported patients , .
notably , he did not have a cleft palate , a feature seen in six of the seven other molecularly confirmed patients .
our patient 's respiratory complications place him on the more severe end of the spectrum of reported patients .
in addition , he had significant failure to thrive requiring hospital admission , supplemental calories and gastrostomy tube placement .
although postnatal growth failure was noted in two of the seven previously reported patients , only one of these two patients was reported to require tube feedings , .
although it is unclear if early postnatal growth issues and failure to thrive are primary features of catel  manzke syndrome , we suspect that our patient 's failure to thrive was secondary to his severe complications from pierre robin sequence because weight gain improved with both gastrostomy and tracheostomy in place .
significant feeding difficulties and failure to thrive are common complications in patients with pierre robin sequence .
tgds encodes dtdp - d - glucose 4,6-dehydratase / growth - inhibiting protein 21 , a protein whose function remains unknown although it has been hypothesized to play a role in proteoglycan metabolism .
the finding of the c.298 g  >  t ( p.ala100ser , rs140430952 ) pathogenic variant in our patient supports the hypothesis of ehmke et al .
that this is the most common pathogenic variant associated with catel  manzke syndrome . taken together ,
the eight reported patients with pathogenic variants in tgds have the c.298 g  >  t variant at an allele frequency of 68.75% .
prior work has suggested that this variant is harbored on a 50  kb haplotype and thus suggests a common founder mutation , found primarily in the european population .
our patient is of mixed european ancestry and previously described patients with this mutation were of german , french , dutch and british / south american ancestry .
a search of the exac database reveals that this variant has been observed 37 times in 121,256 alleles ( allele frequency of 0.0003 ) in the heterozygous state .
in addition to individuals reporting european ethnicity , the variant has also been observed in two individuals with african ethnicity , and one individual with ethnicity described as 
the amino acid substitution is present in the predicted nad binding domain , and it is suggested that the mechanism is loss of function .
the absence of individuals with this variant in the homozygous state in the exac database provides further evidence of the pathogenicity .
our patient is on the severe end of the spectrum of previously reported patients with respiratory complications and failure to thrive requiring gastrostomy tube placement , supplemental calories , and tracheostomy but without cleft palate .
our finding of a homozygous p.ala100ser variant in tgds in our patient supports that this is a common mutation in catel  manzke syndrome , and his phenotypic presentation underlies the severe respiratory and growth complications that can occur in association with pierre robin sequence in this disorder .
the following is the supplementary data related to this article.supplemental table 1primers used for sequencing the coding region of tgds .
 catel  manzke syndrome is a rare autosomal recessive disorder characterized by pierre robin sequence with hyperphalangy and clinodactyly of the index finger . recently , 
 homozygous or compound heterozygous pathogenic variants in tgds have been discovered to cause catel  manzke syndrome . here 
 , we describe a 12-month - old male with molecularly confirmed catel  manzke syndrome who presented with pierre robin sequence ( but without cleft palate ) and hyperphalangy , and we compare his phenotype with the seven previously described patients with pathogenic variants in tgds . 
 our patient is on the severe end of the phenotypic spectrum , presenting with respiratory complications and failure to thrive . 
 furthermore , our finding of a homozygous p.ala100ser pathogenic variant in our patient supports that it is a common mutation in catel  manzke syndrome . 