Index Of Suspicion In The Nursery

Abstract

A male infant who has trisomy 21 is born large for gestational age at 36 weeks' gestation to a 40-year-old G4P2 mother. The mother experienced gestational diabetes and hypertension during the pregnancy. The hospital course in the neonatal intensive care unit (NICU) is uneventful. The infant consumes human milk supplemented with formula every 3 hours. Due to decreased intake, nutritional supplementation by nasogastric tube is initiated. He requires 25 to 30 minutes to feed by mouth with chin support and pacing. There is minimal emesis with feedings until 9 days after birth, when he begins vomiting with each feeding.The amount of emesis varies, consists of undigested milk, and is otherwise nonbilious and nonbloody. The infant can tolerate only small amounts of his feedings by either mouth or nasogastric tube before vomiting, but he continues to have two to three bowel movements per day and good urine output. On physical examination, the baby has physical features consistent with trisomy 21, including epicanthal folds, a flat nasal bridge, macroglossia, Brushfield spots, widened space between the first and second toes, single palmar creases, and generalized hypotonia. There is no notable abdominal distention or palpable abdominal masses. The remainder of the examination yields normal results. A radiologic study helps to reveal the diagnosis.A term male infant is admitted to the NICU after difficulty feeding and respiratory distress at 5 hours of age. The baby was born to a 35-year-old G3T2P0A0L2 woman. All maternal laboratory results were negative during prenatal screening, although prenatal ultrasonography during the third trimester showed oligohydramnios and intrauterine growth restriction. The initial evaluation after delivery revealed an asymmetric, small-for-gestational age infant whose birthweight was 2,215 g and Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. On physical examination, the infant exhibited generalized hypotonia, poor suck with excessive oral secretions, symmetric Moro reflex and posture, normal reflexes, and arthrogryposis of the wrists and elbows. No tongue fasciculations were noted. The remainder of the physical examination showed normal results.In the NICU, the infant is placed on bilevel positive airway pressure due to respiratory distress and antibiotics. Initial attempts to feed the baby orally fail due to persistent desaturations and bradycardia during feedings. Results of Toxoplasma, rubella, cytomegalovirus and herpes simplex virus antibody assessment; lumbar puncture; blood and peripheral cultures; and antiacetylcholine receptor antibody assessment are negative. Additional laboratory work documents elevated creatine kinase (CK) of 9,472 units/L, lactate dehydrogenase of 891 units/L, aldolase of 27 units/L, aspartate aminotransferase of 98 units/L, and alanine aminotransferase of 137 units/L. Head computed tomography scan and magnetic resonance imaging yield normal results. By 1 month of age, the infant is weaned to room air, tolerates oral feedings, and is discharged from the hospital with close outpatient monitoring.He continues to have poor tone and feeding difficulties and is admitted to the hospital at 2 and 3 months of age due to respiratory distress. At about 4 months of age, he is readmitted due to poor feeding and worsening hypotonia. His weight remains below the third percentile, he has poor swallowing, and he takes 45 minutes to consume 4 oz of formula. His motor milestones are delayed, but all other milestones are appropriate for age. A test is performed that reveals the diagnosis.An abdominal radiograph documented a “double-bubble” sign (Fig. 1). An upper gastrointestinal radiographic series confirmed a dilated first portion of the duodenum and a high-grade narrowing in the second portion of the duodenum, with only a very small amount of contrast passing into the proximal small loops of bowel (Fig. 2). These findings were suggestive of a high-grade duodenal stenosis.Congenital duodenal obstruction is present in 30% of patients who have trisomy 21. The pregnancy usually is associated with polyhydramnios due to the inability to absorb ingested amniotic fluid. Bilious emesis frequently is seen in a patient who has a high-grade stenosis, although it was not present in this instance. Nonbilious emesis does not rule out duodenal stenosis in a patient who has trisomy 21. Laboratory results may show hypochloremic hypokalemic metabolic alkalosis as a result of persistent vomiting. Duodenal stenosis can take several weeks to present and initially may be associated with normal findings on imaging. Symptoms before progression of the stenosis may be unnoticed throughout infancy, with the initial symptom of feeding intolerance presenting in childhood. The first radiographic test of choice is abdominal radiography, which classically shows a double-bubble sign. This patient's abdominal radiograph 1 day after birth did not demonstrate these findings. When the clinical suspicion is high, instillation of 50 mL of air to provide a source of contrast may aid in revealing a double-bubble sign.The differential diagnosis for persistent vomiting presenting at 9 days after birth includes but is not limited to gastroesophageal reflux disease, paralytic ileus, peritonitis, milk protein allergy, sepsis, meningitis, hydrocephalus, subdural hematoma, cerebral edema, metabolic disorders, renal insufficiency, obstructive uropathy, pyloric stenosis, intestinal atresias, Hirschsprung disease, annular pancreas, duodenal duplication, esophageal stenosis, duodenal obstruction due to a preduodenal portal vein, and incarcerated hernia. For a patient who has trisomy 21, the potentially higher incidence of anatomic abnormalities such as duodenal stenosis should place these conditions highest on the differential diagnosis.The initial treatment of a patient who has high-grade duodenal stenosis includes decompression of the digestive tract with a nasogastric or oral gastric tube. Intravenous fluid resuscitation should be started. The most common surgical intervention is a repair of the obstruction by a duodenoduodenostomy. Another procedure that may be performed is a duodenojejunostomy. Prognosis is generally favorable, with many patients tolerating initial feedings 1 week following surgery and returning home within 2 to 3 weeks. At the time of operation, a gastrostomy tube may be placed in anticipation of slow progression to full feeding. In this infant, duodenoduodenostomy was performed.The differential diagnosis for a newborn who has feeding intolerance is extensive. Although anatomic abnormalities such as duodenal stenosis are not the most common cause of vomiting in the neonatal population, the increased incidence in infants who have trisomy 21 should lend consideration to this diagnosis. Duodenal stenosis may not present immediately at birth, and if the index of suspicion is high, additional abdominal imaging may be warranted.A muscle biopsy confirmed the diagnosis of congenital muscular dystrophy (CMD), with deficiency of laminin alpha-2 on histochemical staining. There was no family history of any neuromuscular disease. The mother reported that her two other children had a different father and had no medical problems.CMDs are a set of genetically determined conditions in which muscular dystrophy is evident at birth. These dystrophies have been associated with mutations of various genes, including LAMA2, FKRP, LARGE, COL6A1, COL6A2, COL6A3, SEPN1, FCMD, POMGNT1, POMT1, POMT2, ITGA7, and LMNA. The serum CK concentration usually is elevated, and muscle biopsy characteristically is abnormal, with extensive fibrosis, degeneration and regeneration of muscle fibers, and proliferation of fatty and connective tissue.CMD is classified further on the basis of involvement of structural central nervous system (CNS) abnormalities detected by neuroimaging. The absence of structural changes distinguishes “classic” CMD from “syndromic” forms of CMD such as Fukuyama muscular dystrophy, Walker-Warburg syndrome, or muscle-eye-brain disease. However, a few cases of classic CMD with structural lesions have been reported.Classic forms of CMD are identified by mutations within the laminin alpha-2 chain gene. They are subclassified further into merosin-negative and merosin-positive groups. The mode of inheritance is autosomal recessive, and various gene loci such as 6q22−q23, 1q42, 19q13.3, and 1p35−p36, have been reported to be involved.Ullrich congenital muscular dystrophy and Bethlem myopathy are associated with extensive mutations in type VI collagen genes (COL6A1, COL6A2, and COL6A3). Although these conditions previously were believed to be separate entities, they now are considered opposite ends of a phenotypic spectrum. The mode of transmission is autosomal recessive, and there have been associations with genetic mutations on loci 21q22.3 and 2q37.Fukuyama type, muscle-eye-brain disease, and Walker-Warburg syndrome are the types of CMD that typically are associated with CNS abnormalities and are autosomal recessive disorders. The various gene loci involved with these disorders are 9p31–q33, 1p32–p34, 19q13.3, 9q34.1, and 9q31–33. Brain magnetic resonance imaging shows hypodense white matter, hypoplastic cerebellum and pons, ventricular dilatation (with or without hydrocephalus), and abnormal cortical development known as cobblestone type brain malformation (also called type II lissencephaly). Other malformations include Dandy-Walker cyst, sometimes associated with posterior encephaloceles.The infant who has any type of CMD typically presents in the newborn period as a “floppy” baby, often with arthrogryposis. Magnetic resonance imaging of the brain is useful to look for structural lesions or white matter abnormalities that accompany some CMDs. Examination of the eyes is important to exclude an ocular abnormality. Infants who have CMDs have variably elevated serum CK values.Molecular genetic testing allows for confirmation of some forms of CMD, including those associated with mutations in LAMA2, FKRP, POMT1, POMT2, fukutin, POMGnT1, and LARGE1. The diagnosis also can be confirmed by muscle biopsy findings of widespread dystrophic changes or a myopathic pattern. For infants lacking merosin, muscle immunohistochemical examination with antimerosin antibodies usually reveals an absence of this protein in the sarcolemma of the muscle fibers.A child presenting with hypotonia at birth needs to be evaluated for sepsis. The most common infections at birth are TORCH infections. Suggestive history and physical examination findings along with serum and urine evaluation are used to confirm such infections.Certain chromosomal abnormalities such as trisomy 21, Turner syndrome, and Prader-Willi syndrome also present with neonatal hypotonia. Perinatal trauma such as hypoxic-ischemic brain injury and intracranial hemorrhage also is linked with hypotonia at birth. Neuroimaging at birth can aid in establishing this diagnosis.Arthrogryposis in a newborn who has hypotonia usually is due to lower motor neuron lesions after ruling out sepsis and hypoxic-ischemic encephalopathy. Various metabolic and multisystem diseases also are associated with neonatal hypotonia. Glycogen storage diseases, mitochondrial myopathies, peroxisomal disorders, disorders of carnitine metabolism, and congenital myopathies can be seen as well and can be confirmed by muscle biopsy.Various neurologic diseases such as spinal muscular atrophy, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and hereditary sensory and autonomic neuropathy can present with similar symptoms. Electromyography, genetic testing, and muscle biopsy can help in diagnosing these disorders. Neuromuscular junction disorders such as congenital myasthenia should be considered in the differential diagnosis.CMD can present with neonatal hypotonia, arthrogryposis, feeding difficulties, and failure to thrive. Classic types usually are not associated with any CNS malformations on imaging, and syndromic types typically are associated with brain or spinal cord defects. Muscle biopsy is used to confirm the diagnosis, and once the diagnosis is confirmed, supportive treatments such as physical therapy to improve mobility and contractures, mechanical assistance devices for respiratory difficulties, surgery for orthopedic complications, and social and emotional support for the family must be coordinated. Death is usually due to respiratory causes.