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polyhydramnios in the second and third trimester of pregnancy is defined by ( semiquantative ) measurements such as a maximum vertical pocket ( mvp ) > 8 cm , or an amniotic fluid index ( afi ) > 24 cm .
approximately 90% of cases are idiopathic or caused by gestational diabetes ( gdm ) 1 .
most frequent causes are impaired swallowing from any cause ( gastrointestinal , facial , musculoskeletal , or brain abnormalities ) , cardiac failure , hydrops , and renal abnormalities .
metabolic diseases , such as congenital disorders of glycogen storage , are also incidentally reported to present with polyhydramnios in pregnancy 3 .
the usual diagnostic workup of polyhydramnios is to exclude gdm and maternal infections , and to perform an extensive structural assessment to rule out fetal anomalies .
the presence of structural anomalies , involves increased risk of aneuploidy or other chromosomal and syndromic disorders . in isolated polyhydramnios ,
the risk of perinatal adverse outcome is , however , still increased when compared with uneventful pregnancies 4 . a 30yearold primigravid woman , with a so far uneventful pregnancy ,
was referred to our clinic with polyhydramnios . aside from a spontaneously closed ventricular septal defect ( vsd ) in her own infancy , both parents were healthy .
, she presented with signs of polyhydramnios ( uterine size that outpaced gestational age ) and premature contractions .
ultrasound showed polyhydramnios ( mvp 9.9 cm , afi 27.5 cm ) with normal fluidfilled stomach and mild dilatation of both lateral ventricles ( 11 mm ) .
amniotic fluid drainage ( 1.8 l ) was performed in an attempt to cease the premature contractions .
more detailed fetal intracranial assessment was possible afterwards , showing an enlarged cisterna magna ( 12 mm ) and a dysplastic and small cerebellum .
the transcerebellar diameter measured 25.4 mm ( slightly below p3 , with head circumference p50 , fig .
further intracranial assessment was not possible due to maternal habitus , fetal position , and uterine contractions .
qf pcr and a cytoscan hd array were performed , showing a small de novo duplication on chromosome 11 ( 11q22.1 ) , including exon 1 of the contactine 5 ( cntn5 ) gene .
this variant is not reported as genomic variant in the normal population , neither known to be associated with a genetic disorder or malformation .
( a ) fetal cerebral ultrasound at ga 25 + 5 showed cerebellar hypoplasia ( * ) and borderline dilatation of the ventricles .
in retrospect , the outlines of some of the periventricular cysts are also discernible ( see arrows ) .
the bruises around the nose and philtrum , and the asymmetry of the nostrils are the effect of ventilation .
two days later ( 26 + 0 ) , she spontaneously delivered a boy of 835 g ( 0.5 sds ) , apgar scores were 4/4/7 after 1.5 and 10 min , respectively . at birth , he was started on cpap and transported to the neonatal intensive care unit .
he had mild dysmorphic features with high and arched eyebrows , a hairy forehead , triangular face , a slight upslant of palpebral fissures , down turned corners of the mouth , mild hypoplastic alae nasi , prominent pointed chin , deep incisura between tragus and antitragus providing a clear view into the external meatus ( fig .
he had relatively long and slender arms and legs , large hands , long fingers , small fingernails and somewhat broad distal phalanges .
cranial ultrasound on first postnatal day showed bilateral peri and intraventricular hemorrhages with dilatation of the ventricles , periventricular pseudocysts , and confirmed the presence of cerebellar atrophy .
a few hours after birth , the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome .
he developed hypotension and was treated with fluid boluses and inotropic support and antibiotics . despite stabilization of blood pressure and systemic circulation , he developed a progressive lactate acidosis with extremely high plasma lactate : 19.1 mmol / l [ normal range 0.52.2 ] and high pyruvate : 269 mol / l [ normal range 40140 ] .
the l / p ( lactate / pyruvate ) ratio was 71 , which is strongly increased ( normal < 20 ) .
organic acid analysis in urine showed a strong increase of lactate ( 56540 mol / mmol creatinine ) and increases of 3ohbutyrate , pyruvate , fumarate , malate , and 4ohphenyllactate .
oligosaccharides in urine and acylcarnitines and very longchain fatty acids in plasma were normal . in the absence of secondary causes , these findings are consistent with primary lactic acidosis , caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect . due to the severity of the cumulative problems , the neonate died 2 days after birth .
postmortem cranial mri confirmed the findings on ultrasound , showing extensive bilateral intra and periventricular hemorrhage with adjacent cyst ( figure s1c ) , vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst ( figure s1d ) .
dna analysis of the pdha1gene ( most frequent genetic cause of pyruvatedehydrogenase complex deficiency ) showed no pathogenic mutations .
large deletions , point mutations , and small insertions / deletions in mitochondrial dna ( mtdna ) derived from blood were excluded by nextgeneration sequencing ( ngs ) using the illumina miseq platform and a dedicated bioinformatics pipeline ( available on request ) . for whole exome sequencing ,
exome enrichment was performed by the agilent sureselectxt exome enrichment kit version 4 , including the utr regions .
sequencing was performed by an illumina hiseq2000 ( san diego , ca ) using a 2  100 bp pairedend recipe .
basecalling , and demultiplexing was done using bcl2fastq 1.8.4.,(illumina , san diego , ca ) reads were aligned onto the human reference genome ( hg19 ) using bwa 0.5.9 . , duplicates marked using the picard software suite 1.77 ( github enterprise , san francisco , ca ) , and variants were called using gatk 2.18 . annotations were added using an inhouse build annotation database , according to ucsc refgene track , dbsnp137 , and the dbnsfp ( v2.0 ) .
targeted exome analyses of a panel of 447 nuclear genes were performed , containing known mitochondrial disease genes and functionally or clinically related genes .
two heterozygous mutations in the fbxl4 gene were detected and confirmed by sanger sequencing : c.292c > t ( p.(arg98*))and c.1303c > t ( p.(arg435 * ) ) .
both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the fbxl4 protein , respectively . the location of these mutations on different alleles ( compound heterozygosity )
missense and stop mutations in the fbxl4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5 , 6 , 7 , 8 .
our case is the first case demonstrating a premature prenatal onset of symptoms of fbxl4related mitochondrial encephalomyopathy .
the polyhydramnios was the primary sign , leading to the detection of brain abnormalities on more detailed fetal ultrasound examination .
this early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements .
the cases of fbxl4related encephalopathy reported so far are characterized by increased serum lactate level , psychomotor delay , hypotonia , failure to thrive , swallowing difficulty , and muscle wasting 6 .
onset of symptoms varied from neonatal onset after term birth , to the age of 14 months 5 , 6 , 8 .
other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5 , 6 .
the fbxl4 mitochondrial protein contains an fbox in its nterminal half , followed by 11 leucinerich repeats 9 , and is expressed in heart , kidney , liver , lung , pancreas , and placenta 10 .
evidence of the pathogenetic effect of fbxl4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities , loss of mitochondrial membrane potential , a disturbance of the dynamic mitochondrial network , and mtdna depletion 5 .
the nonsense mutation p.arg435 * in the fbxl4 gene , present in our patient , was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy , severe hypotonia , cardiomyopathy , mri abnormalities , increased serum lactate , and premature death 5 .
the second mutation detected in our patient ( p.arg98 * mutation ) has not been reported previously .
however , like the other mutation reported , this nonsense mutation leads to nonsensemediated decay ( nmd , rna degradation ) or a truncated protein 5 , 6 . as a result
the mother was pregnant again before exome sequencing had started . within the prenatal timeframe , exome sequencing lead to the diagnosis of the first child , consequently enabling prenatal diagnosis for the second child .
the vsd in our patient is considered to be a separate finding ( familial trait ) , which is not related to the syndrome .
our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios , causing premature delivery , and cerebellar atrophy .
the neonate was hypotonic and in a poor condition with need for mechanical ventilation , inotropic support , and persistent lactate acidosis .
targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the fbxl4 gene .
direct testing for mutations in the fbxl4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate .

 figure s1 . c. shows an axial view of the postmortal mri ( t2weighted images ) showing dilated ventricles with bilateral peri and intraventricular hemorrhages and cysts adjacent to the right ventricle ( arrows ) .
d. shows the vermian and cerebellar hypoplasia with enlarged cisterna magna or pseudocyst ( arrow ) .
key clinical messagesevere recessive mitochondrial myopathy caused by fbxl4 gene mutations may present prenatally with polyhydramnios and cerebellar hypoplasia . 
 characteristic dysmorphic features are : high and arched eyebrows , triangular face , a slight upslant of palpebral fissures , and a prominent pointed chin . 
 metabolic investigations invariably show increased serum lactate and pyruvate levels .