Rare etiology of arthrogryposis multiplex congenita at term: congenital cytomegalovirus infection

Introduction

Arthrogryposis multiplex congenita is the presence of multiple congenital contractures of two or more body parts [1]. There are multiple causes for decreased fetal movement (akinesia) and contractures, with neuromuscular disorders being the most common etiology [1], [2]. Prenatal ultrasound findings include intrauterine growth restriction, abdominal calcifications, ventriculomegaly and periventricular calcifications [3], [4]. Fetal akinesia leading to multiple contractures is a rare consequence of congenital cytomegalovirus (CMV) infection. We report a case of intrauterine fetal akinesia and arthrogryposis multiplex congenita delivered at term with subsequent neonatal demise. The patient provided permission for photographs and publication through institutional consent forms.

Case presentation

A 28-year-old primigravida was referred for consultation at 20 weeks’ gestation because of fixed extension of the fingers and clubbed feet on fetal anatomy ultrasound. Maternal and family history was unremarkable, and there was no history of rash or viral illness during pregnancy.

Obstetric ultrasound showed no movement of the extremities, and the bilateral fingers were variably fixed in flexion or extension. There were bilateral clubbed feet (Figure 1A–C). Fetal growth and amniotic fluid were normal. No other abnormalities were visualized.

Figure 1:

Fetal ultrasound findings. (A) Right hand at 20 weeks’ gestation. (B) Left hand at 20 weeks’ gestation. (C) Clubbed foot at 20 weeks’ gestation. (D) Intra-abdominal calcifications at 28 weeks’ gestation.

The mother was counseled regarding the possible etiologies of the fetal akinesia and arthrogryposis, including aneuploidy, genetic disorders, neuromuscular disorders or infection. She declined amniocentesis. Cell free fetal DNA screening was low risk for trisomies 13, 18 or 21 and sex chromosomes (XY).

At 28 weeks + 5 days’ gestation, fetal growth was in the 23^rd percentile by Hadlock growth charts [5], although the biparietal diameter was less than expected, measuring 27 weeks + 1 day. Multiple echogenic foci were newly visualized in the fetal abdomen (Figure 1D). Intracranial structures were normal, and the extremity findings were the same as those previously described. At 31 weeks + 4 days’ gestation, the biparietal diameter demonstrated only 2 weeks of interval growth in a 3-week period, measuring 29 weeks + 0 days, with estimated fetal weight in the 15^th percentile by Hadlock and thoracic circumference at the 3^rd percentile [5]. The abdominal echogenic foci and extremity contractures appeared stable. Similar findings were seen at 34 weeks’ gestation.

Weekly non-stress tests started at 32 weeks. At 37 weeks + 5 days’ gestation, there was interval development of oligohydramnios as defined by an amniotic fluid volume <5 cm, and the patient underwent a cesarean section to deliver a 2684 g male in breech position. Apgar scores were 1 and 5 at 1 and 10 minutes, respectively. Umbilical cord arterial blood gas was pH 7.27, CO2 64 mm Hg, HCO₃ 29 mEq/L and base excess 1.3 mEq/L. The infant was apneic upon initial pediatric resuscitative efforts and was intubated. Newborn exam revealed diminished muscle tone throughout. The upper and lower extremities had fixed contractures, with feet in extreme inversion, wrists hyperextended, fingers hyper-flexed and thumbs everted. There was no spontaneous extremity movement. Despite aggressive mechanical ventilation, severe hypoxemia and inadequate ventilation progressed, and the infant died at 17 hours of age. The immediate cause of death was respiratory failure caused by pulmonary hypoplasia due to fetal akinesia sequence.

Autopsy revealed arthrogryposis multiplex congenita with bilateral clubbed feet, flexion contractures of the elbows and knees, hyperextended metacarpophalangeal and hyperflexed interphalangeal joints of the hands, micrognathia and small chest (Figure 2). There was severe pulmonary hypoplasia. Microscopy of multiple organs (liver kidneys, pancreas, pituitary and thyroid) showed characteristic intranuclear and cytoplasmic inclusions of cytomegalovirus, confirmed by immunohistochemical (IHC) staining with antibody to CMV. The brain showed extensive cerebral white matter astrogliosis and focal pericapillary microcalcifications, with no definite CMV cytopathy. There were no abnormalities of skeletal muscle. The placenta showed multi-focal chronic villitis with plasma cells, hemosiderin, micro-calcifications and CMV cytopathy, also confirmed by IHC (Figure 3). Genetic evaluation revealed a normal male by microarray. The underlying cause of the fetal akinesia sequence and neonatal demise was considered to be congenital CMV infection.

Figure 2:

Autopsy. Newborn autopsy with multiple contractures.

Figure 3:

Pathology microscopy.

(A) Placental villous with chronic villitis, including plasma cells, hemosiderin deposition (brown), and microcalcificiation (arrow). (B) Fibrotic, avascular villous with focal hemosiderin (brown) and atypical CMV cytopathy (arrow). (C) Immunohistochemistry using antibody to CMV, on the same villous shown in B, shows focal intravillous positive staining (arrow, brown). (D) Fetal kidney with characteristic CMV inclusions in multiple cells: abnormal cells are enlarged with purple intra-nuclear inclusions and multiple smaller cytoplasmic inclusions (arrow points to one of the aggregate of abnormal cells).

Discussion

Arthrogryposis multiplex congenital is a clinical diagnosis of multiple contractures present at birth, generally due to fetal akinesia [1], [2]. Incidence is estimated at approximately 1:3000 live births. Determining the etiology for arthrogryposis can be challenging given the multiple potential causes. Primary neurologic abnormalities, such as spinal muscular atrophy or a structural brain malformation affecting fetal muscular tone and movement, account for approximately 70–80% of arthrogryposis. Primary myopathies, such as amyoplasia or congenital myotonic dystrophy, account for approximately 20–30% of congenital arthrogryposis. Less common etiologies include fetal connective tissue or cartilage abnormalities, uterine compression or oligohydramnios resulting in limited space for the fetus to move, vascular compromise of the developing fetal brain, or maternal myasthenia gravis with transplacental passage of acetylcholine receptor antibodies leading to transient neonatal myasthenia and antenatal arthrogryposis [6]. CMV has been described in case reports as a cause of congenital arthrogryposis, but is a very rare finding [7], [8].

Approximately 40,000 infants are born with congenital CMV annually in the US. Only 10% of neonates with CMV have clinical symptoms at birth, with the most common sequelae being sensorineural hearing loss [3], [4]. The sequelae of congenital CMV are more severe when infection is acquired early in pregnancy. There are no antenatal ultrasound findings that are diagnostic of CMV infection. Ultrasound findings, if present, commonly include microcephaly, fetal growth restriction, echogenic bowel, hepatic calcifications, periventricular calcifications, ventriculomegaly and ascites [4]. Postnatal clinical findings include petechiae, jaundice, sensorineural hearing loss, hypotonia, chorioretinitis, hepatosplenomegaly and seizures. The overall mortality among infants with congenital CMV infection is 4–8% within the first year of life.

Antenatal diagnosis of CMV can be challenging. In this case, the only ultrasound findings at the 20-week routine anatomy survey were fetal extremity contractures. As in many cases of congenital CMV, the mother did not provide any history of viral illness during pregnancy. Ultrasound findings did not show findings suggestive of CMV until the third trimester, when lagging fetal head growth and abdominal calcifications were first noted. Amniocentesis was declined, which precluded the antenatal testing of amniotic fluid by polymerase chain reaction (PCR) for CMV. In surviving neonates, a diagnosis of congenital CMV is best confirmed by PCR testing on urine, blood or saliva [3]. In this case of neonatal demise, placental pathology and autopsy were critical in the diagnosis of congenital CMV.

Congenital CMV is a rare cause of arthrogryposis multiplex congenita. When a common neuromuscular etiology cannot be found, it is important to consider this rare diagnosis in the work-up of fetal akinesia and arthrogryposis. Autopsy and placental pathology are important diagnostic modalities in the evaluation of arthrogryposis and unexpected fetal or newborn demise.