Bilateral subdural hygromas and cephalhaematomas in male twins with severe myotubular myopathy caused by a Novel c.431delT (p.Leu144fs) mutation in MTM1 gene

Authors


Dr Tejasvi V Chaudhari, Department of Neonatology, Canberra Hospital, PO Box 11, Woden, ACT 2606, Australia. Fax: +612 6244 3112; email: tejasvi.chaudhari@gmail.com.

Case Report

X-linked myotubular myopathy (XLMTM; MIM# 310400) is a severe congenital muscle disorder caused by mutations in the MTM1 gene. It is characterised by severe hypotonia and generalised muscle weakness in affected males, and is generally a fatal disorder in the neonatal period and early infancy.

Male twins were delivered vaginally at 33 + 4 weeks gestation following onset of preterm labour at a private hospital. Twin 1 was born by vaginal delivery with cephalic presentation; there had been a non-reassuring CTG with a fetal bradycardia. His APGAR scores were 1-3-5 at 1, 5 and 10 min, respectively. He was intubated and resuscitated with two boluses of normal saline for signs and symptoms of shock secondary to extensive bilateral cephalhaematomas. Twin 2 was born vaginally as a footling breech presentation. His APGAR scores were 1-5-5 at 1, 5 and 10 min, respectively. He required resuscitation at birth with intubation and a normal saline bolus because of signs and symptoms of shock as a result of extensive bilateral cephalhaematomas. He also sustained a fractured left femur and right humerus. The preliminary diagnosis at the time of request for retrieval was hypoxic ischaemic encephalopathy.

Twin 1 was administered surfactant prior to transfer to our neonatal intensive care unit. On admission, he was managed with a transfusion of packed red blood cells (PRBCs) for ongoing evidence of shock secondary to blood loss. The coagulation profile was normal. On examination, he displayed marked hypotonia, an absent gag reflex and decreased overall activity. Seizures were noted on amplitude electroencephalogram monitoring and were treated with phenobarbitone (one dose), after which no further seizures were observed. Cranial magnetic resonance imaging (MRI) was performed on day 5 of life and revealed large bilateral subdural hygromas, the cause of which was unclear but may have possibly been secondary to subdural haemorrhages. There was no evidence of hypoxic ischaemic changes.

On admission to the neonatal intensive care unit, twin 2 was managed with PRBCs, fresh frozen plasma, platelets and inotropes for signs and symptoms of shock from extensive blood loss because of the bilateral cephalhaematomas, fractured left femur and right humerus. On examination, he also displayed marked hypotonia, absent gag reflex, decreased overall activity and absent deep tendon reflexes. The initial MRI brain of twin 2 also showed large bilateral cephalhematomas and large subdural hygromas/effusions. As with his sibling, the underlying brain appeared normal with no evidence of hypoxic ischaemic change.

Both twins had decreased muscle mass, temporal scalloping, thin ribs, long fingers and bilateral undescended testes. On further questioning, a history of polyhydramnios with decreased fetal movements in utero was obtained. The physical examination and lack of hypoxic ischaemic change on MRI suggested a neuromuscular disorder. A full metabolic screen revealed no abnormality. Spinal muscular atrophy (SMA) gene mutations for spinal muscular atrophy were not found. Nerve conduction velocity studies on twin 1 were normal.

On day 26, twin 2 deteriorated rapidly with increasing ventilatory requirements. Given the poor prognosis, the parents chose to forego continued intensive care and palliative care was instituted and he died shortly thereafter in his parents' arms. A post-mortem muscle biopsy showed features consistent with centronuclear (e.g. myotubular) myopathy. On light microscopy, the majority of fibres were small, with occasional central nuclei. On electron microscopy, approximately 30% of muscle fibres had centrally located nuclei and mitochondria. In additional fibres, Z-band streaming and loss of sarcomere organisation was readily apparent. Cytogenetics showed a male karyotype with no cytogenetic abnormality. DNA was sent for molecular studies of the MTM1 gene. A direct sequence analysis of the entire coding region of the MTM1 gene identified a hemizygous deletion of the T nucleotide at position 431 in exon 6 (c.431delT [p.Leu144fs]), which results in frameshift at codon 144.

Twin 1 was eventually successfully extubated to continuous positive airway pressure (CPAP) on day 43 of life. A repeat MRI of the brain showed bilateral cephalhematomas, a prominent left cisterna magna but no focal brain abnormality was identified. Several attempts to wean from CPAP were unsuccessful. Extensive discussions were held with his parents because of the poor long-term prognosis. On day 69 of life, a decision was made for palliative care management and he died peacefully in his parents, arms later that day. Zygosity studies of the twins revealed that they were monozygous.

Key Points

  • 1X linked myotubular myopathy is a rare neuromuscular disorder which may present in the newborn as hypoxic ischaemic encephalopathy.
  • 2Clinical manifestations like hypotonia and lethargy in newborn must be evaluated diligently and may point towards underlying neuromuscular and metabolic disorder.
  • 3Myotubular myopathy may be associated with subdural hygromas and cephalhaematomas.

Discussion

X-linked myotubular myopathy is a severe muscular disease characterised by neonatal hypotonia, severe global muscular weakness and respiratory distress in affected males. Carrier females rarely show clinical signs. The majority of patients die during the first year of life, although prolonged survival is observed in milder forms, or as a result of prolonged ventilatory support. Survivors do not experience a progressive course but have major physical handicaps, rarely walk and remain severely hypotonic.1 Neonates with neuromuscular disorders may appear to have an initial diagnosis of hypoxic ischaemic encephalopathy at birth, and careful examination is required to ensure that neuromuscular conditions are not missed.

Muscle histopathology shows small rounded fibres with centrally located nuclei surrounded by a perinuclear halo. These fibres resemble fetal myotubes, and thus suggest that impaired muscle maturation is the underlying pathology.2,3

MTM1 gene mutation, which is responsible for myotubular myopathy, is located on Xq28 and was identified in 1996 by positional cloning. MTM1 contains 15 exons over 100 kb. It encodes a protein, myotubularin, which belongs to a putative tyrosine phosphatase family.4 To date, mutations have been reported in 251 unrelated families, corresponding to 158 different disease-associated mutations, which are widespread throughout the gene.5,6 While truncating mutations cause, in almost all cases, the severe neonatal form, some missense mutations are associated with milder forms, which may allow survival to adult age. Although our mutation is novel, it is considered to be pathogenic, as a mutation at a different base causing the same amino acid change (c.426delT [p.Leu144fs]) was described by Tanner et al. as a cause of severe myotubular myopathy.6 These are the first cases of myotubular myopathy associated with subdural hygromas and extensive cephalhaematomas. Given that the twins were monozygotic in origin, diamniotic dichorionic placentation may have occurred as a result of early splitting. No mutation was identified in the mother and we assume that the condition occurred as a new mutation or as a result of gonadal mosaicism.

These cases highlight that neuromuscular disorders may initially present as hypoxic ischaemic encephalopathy in the neonate. With a multidisciplinary team approach, appropriate investigations can be arranged so that a diagnosis can be found and risks identified for future pregnancies.

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