Clinical study of a patient with congenital myotonic dystrophy reveals chylothorax as neonatal presentation of the disease

Introduction

Myotonic dystrophy type 1 (DM1) is a multisystem disease whose most prominent manifestations are myotonia, atrophy and progressive weakness of the neuromuscular systems. DM1 is an autosomal dominant condition caused by an expansion of an unstable CTG trinucleotide repeat in the 3′ untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Normal individuals have between five and 37 CTG repeats whereas alleles greater than 37 repeats are unstable and may expand in length during mitosis and meiosis. The resulting pathological expansion is associated with an increase of disease severity and age of onset in successive generations (anticipation phenomenon) [1].

The phenotype of DM1 is variable and encompasses a broad spectrum of severity including mild forms, classical adult, childhood and congenital. It is the most common adult muscular dystrophy, with an estimated worldwide prevalence of 1 in 8000 [1]. Congenital myotonic dystrophy (CMD), the most severe form, is often a life-threatening condition. It is characterized by severe hypotonia and weakness at birth, usually with respiratory insufficiency and feeding problems. The incidence of CMD is up to 1 in about 50,000 live births, and mortality in the neonatal period may be up to 40% [1].

While the clinical manifestations and natural history of DM1 in adulthood are well established, manifestations of neonatal DM1 warrant further evaluation [1]. It is critical to develop a better and focused understanding of the unique issues encountered in the management of DM1 in neonatology protocols to improve outcomes and develop standards of care.

Here, we report on the clinical and molecular findings of a female neonate with prenatal congenital chylothorax (CC) diagnosed with myotonic dystrophy. We also review the association of chylothorax or pleural effusion as first manifestation of a congenital severe myopathy.

Case report

The proband was the first child of a non-consanguineous couple. The pregnancy was initially uneventful. However, an ultrasound examination at the third trimester showed polyhydramnios (lung-to-head ratio 1.27). Polyhydramnios amniodrainage was required 3 times (volumes of 1500, 3200 and 1700 mL at the 28^th, 31^st and 33^rd weeks, respectively). At the 35th week of pregnancy, an arthrogrypotic attitude was detected with foot malposition and lack of knee flexion. Corticosteroid treatment was administered to induce lung maturation.

She was delivered preterm at 36 + 2 weeks by cesarean section because of fetal distress, with an Apgar score of 0 at 1 min and 3 at 5 min. At birth she showed no respiratory effort, no movement and generalized cyanosis, so she was resuscitated with intubation. At birth she weighed 2500 g (−0.5 standard deviation [SD]), measured 48 cm (+0.7 SD), and presented an occipital-facial circumference of 35 cm (+2.3 SD). Examination at birth revealed the presence of generalized edema predominantly in the thorax and in the head. Her face was expressionless and triangular with low set ears and an inverted V-shaped upper lip. Severe, generalized hypotonia was notable. Primitive reflexes were not induced.

A chest radiograph a few hours after birth showed a right pleural effusion, which evolved to bilateral in the following days and was managed by bilateral chest tube drainage. Laboratory examination was compatible with a highly productive chylothorax (100–120 mL/kg/day). No other malformations were found in the abdominal ultrasound. Electromyography (EMG) provided evidence of severe congenital myopathy, but did not allow for a specific diagnosis. A muscle biopsy was obtained. The respiratory problems of the patient progressively worsened and she finally died at 2 weeks old. Muscle biopsy findings oriented a possible diagnosis of myotubular myopathy (Figure 1), a genetically heterogeneous disorder that includes an X-linked form. Given that the patient was a female, skewed inactivation due to methylation of the AR gene was excluded. Subsequent testing of the DNM2 and BIN1 genes was negative. CMD, a disorder that is considered in the differential diagnosis was also studied. PCR-Southern DNA analysis using a biotin-(CTG)₁₀ probe revealed, a CTG expansion of more than 750 repeats, thus confirming the diagnosis of CMD (DM1). The father, who was asymptomatic, had both normal alleles. The mother, aged 25 years, showed a CTG repeat length of about 600 but without noticeable clinical manifestations. Only minimal EMG findings were detected in a subsequent follow-up. Appropriate genetic counseling was provided to the couple.

Figure 1:

Quadriceps muscle biopsy showing small and rounded fibers with large and central nuclei in hematoxylin-eosin (H&E) stains. (A, 200×; B, 400×). Neither nemaline rods nor ragged red fibers were found on modified Gömöri trichrome stain (C, 200×). On oxidative enzyme staining, fibers displayed a dark center and a peripheral halo. Muscle fibers were predominantly of type I (dark on ATPase at pH 4).

Discussion

CMD gestation is often complicated by polyhydramnios, reduced fetal movements and preterm delivery. Ultrasonographic diagnosis of middle trimester polyhydramnios should indicate a search for associated fetal anomalies that could indicate an increased risk for CMD. The most prominent ultrasonographic finding in CMD fetuses are contractures, which were not present in our patient [2].

Usually, neonates with CMD are born with hypotonia and immobility, bilateral club foot, contractures, arthrogryposis, facial dysmorphism (carp mouth, ptosis, long neck and face, temporal muscle atrophy), hyporeflexia, weak cry, as well as sucking, swallowing and respiratory difficulties. Cases of premature (<36 weeks' gestation) and small for gestational age CMD newborns have also been reported [1]. Respiratory distress is found in about 50% of neonates, and is used to distinguish mild from severe cases [2]. It is the main cause of CMD-associated neonatal mortality, as it accounts for 30–40% of all CMD cases [1], [2].

An unusual feature in our patient was the presence of CC, which is usually defined as the accumulation of intestinal lymph in the pleural space. Although the estimated prevalence of CC is low, ranging from 1:8600 to 1:10,000 live births, it is the most common cause of congenital pleural effusion during the neonatal period [2]. Regarding its etiology, traumatic (post-surgical and nonsurgical) and nontraumatic forms have been described [2]. CC with or without hydrops has been reported in few cases of CMD [3], [4], [5] and other severe forms of congenital myopathy (Table 1) [6], [7], [8], [9].

Development of tissue edema is prevented, in most organs, by the lymphatic system [10]. Lymphatic vessels devoid of smooth muscles rely on tissue motion to form the lymph and propel it along the lymphatic network. Active muscle contraction is required to support an efficient lymphatic drainage. Thus, tissue motion and biomechanical forces play a fundamental role in lymph formation and circulation, and both are impaired in CMD and other severe congenital myopathies [3], [4], [5], [6], [7], [8], [9].

Congenital myopathy should be considered as part of the differential diagnosis in all cases of severe generalized weakness with chylothorax or pleural effusion and/or hydrops (Table 1). In particular, CMD should be considered by frequency and the presence of some typical findings such as severe hypotonia, marked joint hypermobility and typical facial features.