摘要
A female infant is born via cesarean delivery at 35 weeks’ gestation to a 20-year-old gravida 3, para 2 woman who has a history of 1 spontaneous abortion and 1 neonate who died soon after birth because of respiratory failure of unknown etiology. Antenatal history is significant for fetal growth restriction and polyhydramnios, as well as pregnancy-induced hypertension and hypothyroidism, for which she is currently on medications (labetalol and L-thyroxine, respectively). There is a history of second-degree consanguinity.The infant is born with a birthweight of 1.8 kg (3rd percentile), with Apgar scores of 2, 6, and 8 at 1, 5, and 10 minutes, respectively. She requires intubation in the delivery room for weak respiratory effort. Physical examination shows mild atypical features such as low-set ears, high-arched palate, frontal bossing, and micrognathia. She has persistent severe hypotonia with an absence of palmar grasp reflex and deep tendon reflexes, though her sensorium improves after the initiation of ventilation. Her light reflex and ocular movements are normal. On the second day after birth, she can move her shoulder and hip joints but remains severely hypotonic.Her laboratory tests are as follows: Complete blood cell count: White blood cell count of 10,800/µL (10.8 × 109/L), hemoglobin of 18.3 g/dL (183 g/L), platelet count of 216 × 103/µL (216 × 109/L)Activated partial thromboplastin time: 100 seconds, prothrombin time: 18 secondsBlood gas after intubation: pH of 7.27, Pco2 of 45 mm Hg (6 kPa), bicarbonate of 20 mEq/L (20 mmol/L), base excess of −6 mmol/L (no cord gas analysis available)Blood ammonia: 146 µg/dL (104.24 µmol/L)Serum lactate: 23 mg/dL (2.55 mmol/L)Creatinine phosphokinase (CPK): 94 U/L (1.57 µkat/L)Immunoglobulin M for congenital infections (toxoplasmosis, rubella, cytomegalovirus, and herpes): NegativeA chest radiograph is obtained when the infant is 2 hours of age (Fig). Magnetic resonance imaging findings of the brain are normal. She undergoes extubation and is transitioned from low ventilator settings to bubble continuous positive airway pressure at 20 hours of age. She develops increased work of breathing and desaturations immediately after extubation (Video) and requires reintubation. Orogastric feedings are started at 3 days of age.The initial differential diagnoses for this term infant with severe hypotonia and respiratory failure that we considered were as follows: Hypoxic-ischemic encephalopathy (HIE)Spinal muscular atrophy (SMA)Congenital muscular dystrophyInfants with HIE have clinical signs of encephalopathy rather than weakness. Hypotonia could be the presenting sign of HIE, but in this case, a blood gas at 1 hour of age showed no acidosis, and there was no perinatal event. The infant’s physical examination findings of high arched palate, low-set ears, hypotonia, and lack of acidosis, and the family history of consanguinity and previous newborn death, make a genetic disorder more likely.SMA occurs because of a mutation in the SMN1 gene that encodes SMN, a protein essential for the survival of motor neurons. (1) Another gene, SMN2, determines the severity of the disease course. Infants with type 0 (prenatal) SMA present at birth with muscle weakness, areflexia, feeding difficulties, and respiratory muscle weakness, surviving for only a few weeks. (1) SMA type 1 manifests in the first few weeks or months after birth with hypotonia and progressive muscle weakness. Weakness involves the proximal muscles predominantly more than the distal muscles. (1)Congenital muscular dystrophy presents at birth or in infancy with hypotonia, joint laxity, and congenital contractures. Affected infants may have cranial malformations and eye abnormalities. Affected infants also have elevated CPK levels, which makes a diagnosis of congenital muscular dystrophy in this patient less likely. (2)The infant developed stridor and a large amount of oral secretions. As a result, a direct laryngoscopic examination was conducted, which revealed an absent gag reflex with pooling of secretions and a flickering movement of the left vocal cord with right vocal cord palsy. The presence of profound hypotonia, distal muscle weakness, areflexia, cranial nerve involvement (evident by the absence of gag reflex and vocal cord paresis) with normal CPK levels, and a prenatal history of polyhydramnios was suggestive of congenital hypomyelinating neuropathy (CHN). The genetics team was consulted, and whole exome sequencing was sent at 4 days of age.The infant had repeated extubation failures because of poor respiratory drive and finally succumbed to aspiration pneumonia before the completion of nerve conduction velocity studies and electromyography.Whole exome sequencing showed a homozygous missense variation in exon 20 of the CNTNAP1 (contact-associated protein 1) gene (chr17:g.42696126C>T), resulting in the amino acid substitution of cysteine for arginine at codon 1150. The heterozygous variant C/T was detected at c.3448C>T position in the CNTNAP1 gene for both parents, which confirmed the diagnosis of CHN3.CHN3 is a rare neurologic disorder caused by homozygous or compound heterozygous mutation in the CNTNAP1 gene that is involved in the organization of the paranodal domain of axons. (3) It has an autosomal recessive pattern of inheritance with the onset of neurogenic muscle weakness in utero. It is associated with polyhydramnios and preterm labor. (4)The clinical features of CHN3 consist of profound hypotonia at birth, respiratory insufficiency, and feeding difficulties. Some newborns may present with severe contractures at birth. Atypical facial features include microcephaly, low-set ears, high-arched palate, cleft palate, facial diplegia, ptosis, gingival hyperplasia, and micrognathia. The other findings are clubfoot, scoliosis, visual impairment, and hearing loss. (5) Right diaphragmatic paralysis, left vocal cord palsy, and repeated extubation failure are reported in infants with CHN. (6)Classic for this condition, nerve conduction velocities are markedly decreased at less than 10 m/s. (7) Sural nerve biopsy shows less or absent myelination. Magnetic resonance imaging of the brain shows central hypomyelination, cerebral, and cerebellar atrophy. Prognosis is poor because most affected infants die in the first year of age as a result of respiratory compromise; those who survive suffer from severe psychomotor impairment. (8) Whole exome sequencing helps establish an early diagnosis of this rare disorder so that clinicians can counsel parents of the affected infants about the natural course of this disorder. This genetic testing provides an opportunity for the parents to get tested to determine the risks of recurrence in future pregnancies.Consider a central nervous system etiology in extubation failure of a neonate with stridor, pooling of oral secretions, and respiratory distress as well as clear lung fields on chest radiography.The presence of hypotonia, areflexia, cranial nerve involvement, and respiratory failure suggests CHN.CHN3 is an autosomal recessive condition with a poor prognosis. Whole exome sequencing aids in the early diagnosis of this disorder and assists with genetic counseling.We thank Dr Raeshmi, Dr Sasi Anand, consultant pediatricians, Ramalingam Hospital, Salem, Tamil Nadu, India, and Dr Kanagarathnam, DGO (Diploma in Gynaecology and Obstetrics), Shri Ramana Polyclinic, Salem, for patient management.