Index of Suspicion in the Nursery

Abstract

A term male infant is transferred to the NICU for persistent hypoglycemia at age 3.5 hours. The infant had a blood sugar level of 21 mg/dL at age 3 hours and despite refeeding 20 mL of 20 calories per ounce of formula, his blood glucose level remained at 20 mg/dL at 3.5 hours.The infant was born via cesarean delivery for a nonreassuring heart rate tracing to a 19-year-old G1P 0 African-American mother. All prenatal laboratory results were negative, including an oral glucose tolerance test. Prenatal ultrasonography was performed during the second trimester and showed no gross fetal anomalies other than the presence of a two-vessel cord.The infant cried spontaneously at birth and had some transient respiratory distress. The infant weighs 2,960 g (50th percentile) with a length of 48 cm (50th percentile) and a head circumference of 32.5 cm (25th–50th percentile). Results of the physical examination are normal except for a small penis (stretched penile length of 1.5 cm, width of 0.6 cm) and an undescended left testicle. Blood glucose levels below 40 mg/dL persist despite two boluses of 10% dextrose and administration of continuous dextrose infusion with a glucose infusion rate of ∼5 mg/kg per minute. Glucose levels above 40 mg/dL are eventually achieved with a glucose infusion rate of 8 mg/kg per minute.The pediatric endocrinology service was consulted on the second day for persistent hypoglycemia.A 3,490-g term male infant is born to a 20-year-old primigravida mother. She received good prenatal care, and her pregnancy was uncomplicated. Antenatal screening for human immunodeficiency virus, hepatitis B, and syphilis were negative, and she had immunity against rubella. Results of the patient’s cervical culture were positive for group B streptococcus, but she received adequate intrapartum penicillin prophylaxis before delivery. There was no abnormality noted on the fetal cardiotocography.The infant is delivered by spontaneous vaginal delivery through meconium-stained amniotic fluid and has no respiratory effort immediately after birth. He is intubated, and meconium is suctioned from below the vocal cord. The infant then has spontaneous respiratory efforts and is extubated. The Apgar scores were 4, 6, and 8 at 1, 5, and 10 minutes, respectively. He is transferred to the NICU on supplemental oxygen. Shortly after arrival in the NICU, he develops an inspiratory stridor, and free flow oxygen is given.At 30 minutes after birth, the infant has an apneic episode. He is intubated and placed on mechanical ventilation. Blood is drawn for culture and complete blood count, and he is started on ampicillin and gentamicin.At 11 hours after birth, the infant self-extubates and is weaned to high-flow nasal cannula. The infant is noted to have inspiratory stridor and receives 1 dose of dexamethasone (Fig 2). He is weaned to room air after 3 days. He continues to have loud biphasic inspiratory stridor along with subcostal, suprasternal, and intercostal retractions during this period for which the pediatric otolaryngologist is consulted.The differential diagnosis of hypoglycemia in the newborn is very broad and includes prematurity, intrauterine growth retardation, infant of a diabetic mother, hypothermia, perinatal asphyxia, and sepsis. These entities were quickly ruled out given the negative history and physical examination. Disorders of gluconeogenesis/glycogenolysis, hyperinsulinism, and primary and secondary adrenal insufficiency were then considered, especially in the context of the physical finding of a micropenis.Common causes of micropenis (microphallus) in a newborn include hypogonadotropic hypogonadism from pituitary and hypothalamic lesions, hypergonadotropic hypogonadism (primary testicular failure), septo-optic dysplasia sequence, Smith-Lemli-Opitz syndrome, Kallmann syndrome, and Prader-Willi syndrome. Micropenis is often associated with major chromosomal defects, including Klinefelter syndrome (47,XXY) as well as other X polysomy syndromes, and translocations, deletions, and trisomy involving chromosomes 8, 13, and 18. An apparent micropenis could also result from the virilization of the female external genitalia in cases of congenital adrenal hypoplasia due to 21α-hydroxylase and 11β-hydroxylase deficiency.A pelvic and renal ultrasound is performed on day 2 due to the presence of the two-vessel cord as well as the undescended testicle. No evidence of hydronephrosis or other renal malformations are found. The pelvic ultrasound confirms the bilateral presence of testes in the inguinal canal and the absence of a uterine cavity. At age 60 hours, the infant is noted to have an elevated serum bilirubin level of 13.0/0.3 mg/dL, and treatment with phototherapy is begun. Hyperbilirubinemia resolves by age 90 hours.An magnetic resonance imaging (MRI) of the brain is performed without intravenous contrast. Axial and sagittal T1-weighted, transaxial T2-weighted, transaxial FLAIR, and echo-planar diffusion-weighted pulse sequences are done. Ectopic location of the pituitary bright spot is seen in the region of the hypothalamus, signifying an ectopic posterior pituitary (Fig 1). The pituitary infundibulum is not identified. No mass effect or midline shift is noted.Endocrine laboratory results on day 2 are shown in the Table.The diagnosis is congenital hypopituitarism.Hypopituitarism denotes underproduction, deficiency, or lack of secretion of more than one anterior pituitary hormone. The incidence of congenital hypopituitarism is thought to be between 1 in 4,000 and 1 in 10,000 live births. Defects in the genes that encode the transcription factors such as PROP1, POU1F1, LHX3, LHX4, and HESX1, which are necessary for the differentiation of anterior pituitary cells, have recently been found to be responsible for the development of congenital hypopituitarism. The likelihood of finding mutations is increased by a positive family history, with gene mutations found in 13% of isolated growth hormone (GH) deficiency and 20% of multiple pituitary hormone deficiency cases.The clinical manifestations of hypopituitarism depend on which anterior pituitary hormones are deficient. Severe prenatal deficiency of GH, as occurs in congenital hypopituitarism, has little effect on fetal growth because in utero growth is dependent on insulin, insulin growth factor-1 (IGF-1), and insulin growth factor-2. It does, however, present as micropenis, especially when gonadotropins are also deficient. In addition to micropenis in males, additional consequences of severe GH deficiency in the first days after birth may include hypoglycemia and exaggerated jaundice (both direct and indirect hyperbilirubinemia). Symptoms of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency in a newborn male can also cause micropenis, testicular hypofunction, and undescended testis. LH in utero is important for the stimulation of the LH/choriogonadotropin receptor, which leads to testosterone synthesis in the Leydig cells and plays an important role in the descent of the testes. Gonadotropin deficiency in males subsequently leads to testosterone deficiency, infertility, and osteopenia/osteoporosis. In females, there are no obvious manifestations of gonadotropin deficiency in the neonatal period, but eventually in adolescents, it leads to failure of pubertal development, primary amenorrhea, and infertility.The presentation of adrenorticotropic hormone (ACTH) deficiency is almost exclusively related to glucocorticoid (cortisol) deficiency resulting in hypoglycemia. Of note is that ACTH deficiency does not cause salt wasting and hyperkalemia because it does not result in deficiency of aldosterone. The clinical manifestations of thyroid-stimulating hormone (TSH) deficiency are similar to those of primary hypothyroidism. Large fontanels, lethargy, constipation, hoarse cry, hypotonia, hypothermia, and jaundice are known to occur if thyroid replacement therapy is not promptly started. Symptoms usually develop within the first 2 weeks and are almost always present by 6 weeks.The diagnosis of panhypopituitarism is the sum of the clinical findings of micropenis, undescended testes, persistent hypoglycemia, and prolonged jaundice, along with laboratory evaluation of each pituitary hormonal axis such as ACTH–cortisol, TSH–freeT4, GH–IGF-1, and LH, FSH–testosterone, and an MRI of the pituitary gland. The review of the endocrine laboratory values in this case shows low concentrations of cortisol and undetectable levels of ACTH. Free T4 levels are also low, which is consistent with central hypothyroidism. The TSH concentrations are generally low but sometimes can be in the normal range, as in our case. The IGF-1 levels were undetectable. Unstimulated GH levels are not useful for aiding in the diagnosis of GH deficiency, but the undetectable levels of IGF-1 are consistent with GH deficiency. The gonadotrophins, LH and FSH, start to rise to pubertal levels at age 2 weeks as part of a postnatal surge. LH and FSH levels, which were repeated at 2 weeks, were low; this finding is also consistent with gonadotropin deficiency. A formal evaluation of gonadotropin deficiency with a Lupron stimulation test will be done in the future.The posterior pituitary seems to be functioning because serum sodium levels have remained normal and the pituitary bright spot is identified, consistent with the presence of arginine vasopressin–producing cells. The combination of anterior pituitary hormone deficiencies along with the MRI finding of an ectopic posterior pituitary points toward a defect in one of the transcriptional factors necessary for pituitary development. Any such factor is yet to be investigated and identified in this patient. The investigation of genetic diagnosis is imperative in these cases; the family should undergo genetic counseling, and the first-degree family members should be analyzed for genetic mutations as well. If the mutation occurred de novo in this patient, then the chances of panhypopituitarism in another sibling are low compared with an autosomal recessive or autosomal dominant trait. Patients who have transcription factor deficiency have also been reported to present with developmental, motor, and speech delays.Treatment of panhypopituitarism involves the replacement of each deficient pituitary hormone. The patient may also require surgical correction of undescended testis along with human chorionic gonadotropin or short-term androgen treatment, which aids in the descent and improvement of micropenis. Some patients who have panhypopituitarism may also require early intervention services for physical, speech, and occupational therapy.In our patient, hydrocortisone is started at a dose of 2.5 mg three times a day on day 2 due to low cortisol levels, which is later increased to 5 mg three times a day (supraphysiological dose) due to the persistence of hypoglycemia. Levothyroxine (12.5 μg orally daily) is started on day 3 for hypothyroidism secondary to a repeat low free T4 level. GH (0.1 mg subcutaneously daily [ie, 0.3 mg/kg per week]) is started on day 4 due to low IGF-1 levels, the findings of micropenis, and the persistence of intermittent hypoglycemia despite a supraphysiological dose of hydrocortisone. Before discharge, the patient’s parents are taught how to use a glucometer and how to recognize the signs of adrenal insufficiency. The infant is discharged from the hospital with supplies of glucagon and Solu-Cortef® (Pfizer Inc., New York, NY) emergency kits. The parents are also instructed to increase the dose of hydrocortisone during periods of stress and fever. Gonadotropin and sex steroid replacement will be started at the time of initiation of puberty and adolescence.The diagnosis in this case is right vocal cord paralysis (VCP).Assessment of upper airway by an otolaryngologist revealed bilateral patent nasal choanae, normal nasopharynx, and oropharynx. Immobility of the right true vocal cord from the level of the right arytenoids was noted. The left vocal cord was normal.A CT scan of the head and neck soft tissue and an MRI of the brain were normal. An MRI of the neck showed diffuse edema of bilateral true and false vocal cords. Supraglottic and infraglottic portions of the larynx were unremarkable. No mass lesion was seen along the course of either of the recurrent laryngeal nerve. There was a left-sided aortic arch with no vascular ring. Flexible and direct laryngoscopy along with rigid bronchoscopy revealed significant supraglottic edema of the vocal cords and arytenoids, and immobility of the right vocal cord with paradoxical movement of the left vocal cord with adduction on inspiration. There was no laryngotracheobronchomalacia. Results of the video swallow study were normal. Dexamethasone was started and tapered off gradually. The stridor gradually improved, and the infant was able to tolerate full oral feeds. He is currently stable without any stridor and is being followed up by multidisciplinary team.Stridor is caused by the oscillation of a narrow airway, suggesting obstruction of large airways. Congenital stridor is an uncommon presentation of respiratory distress at birth. Differential diagnosis of congenital stridor includes laryngomalacia, VCP, congenital subglottic stenosis, and various other anatomical abnormalities of the upper airways and surrounding structures. VCP is the second most common cause of congenital stridor and is responsible for 10% of all laryngeal congenital abnormalities. (1)VCP can be congenital or acquired, and it can be unilateral or bilateral. The most common cause of VCP is idiopathic. Arnold-Chiari malformation is the most common central nervous system anomaly that may cause bilateral VCP. (2) The most common cause of acquired VCP is iatrogenic injury to left recurrent laryngeal nerve during ligation of patent ductus arteriosus (PDA). (3) In such cases, patients present with difficulty breathing and dysphonia. Unilateral VCP is most often associated with birth trauma and is often temporary; however, bilateral VCP is associated with other anomalies. When VCP occurs after endotracheal intubation, it is due to peripheral nerve damage caused by nerve compression between the inflated endotracheal tube cuff and the thyroid cartilage at the junction of the vocal process of the arytenoid cartilage and the membranous vocal cord. (4) VCP after endotracheal intubation is temporary and resolves spontaneously by age 6 months. Diagnosis of VCP is often very difficult, but in a neonate who has a history of a high-pitched inspiratory stridor and respiratory problems, a diagnosis of bilateral abductor VCP is more common, especially in association with Arnold-Chiari malformation, tracheoesophageal fistula, or vascular rings. (5) In a young infant who has a hoarse voice, low-pitched cry, or breathy cry or voice, it is most likely a unilateral vocal cord paresis or paralysis (4). If these symptoms occur after a surgical repair of a PDA or tracheoesophageal fistula, a unilateral VCP is the diagnosis until proven otherwise. The most common way to make the diagnosis is via a flexible fiberoptic nasopharyngolaryngoscope and photodocumentation using a videocassette recorder. (3) Other studies such as CT scans or MRIs can also be performed. It has been suggested that to allow for early diagnosis of VCP, a presurgical and postsurgical flexible fiberoptic laryngoscopy may be helpful in neonates for whom cardiac surgery is indicated to correct congenital cardiac abnormalities. (2)When the diagnosis is made, a swallow study should be obtained because of the risk of aspiration with feeding. If aspiration occurs with thin liquids, feedings may be thickened or a gastrostomy tube may have to be placed. (3) Prognosis is dependent on the etiology of the VCP. If it is due to a stretch, intubation, or partial trauma to the recurrent laryngeal nerve, time may be the healing factor to the cord. If the recurrent laryngeal nerve is totally transected, a regain of function may be unlikely. When VCP is postoperative, it is mostly unilateral, and vocal cord function may improve over time due to the pliability of the glottis and compensation from the unaffected cord because it can cross the midline to achieve compensatory glottis closure. (4)It is recommended that patients should follow up with a pediatric otolaryngologist every 3 months for the first year after the diagnosis is made, and then every 6 months the next year and every year thereafter. (1)