A 4-month-old girl arrives at the clinic for a well-child visit. Her mother voices concerns about the infant’s poor weight gain, slow feeding habits, and physical delays such as head lag, poor grasp reflex, and rolling over.
A 4-month-old girl arrives at the clinic for a well-child visit. Her mother voices concerns about the infant’s poor weight gain, slow feeding habits, and physical delays such as head lag, poor grasp reflex, and rolling over. The mother is in the military and getting ready to be deployed; the father had abandoned her when he learned of the pregnancy. The maternal grandmother plans to care for the infant until the mother returns from her tour of duty.
The infant was born to a 30-year-old primigravida mother at 39 weeks via spontaneous vaginal delivery. Although the pregnancy was unplanned, the mother had regular prenatal care and was negative for gonorrhea, chlamydia, and human immunodeficiency virus (HIV) infection. Birth weight was appropriate for gestational age (2.78 kg), and the infant’s Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. There was no hypotonia noted during her nursery stay, and there were no concerns for inadequate suck or for jaundice. At discharge from the nursery, she weighed 2.49 kg, a 10% weight loss from her birth weight.
At the 2-week visit, the patient had not regained her birth weight; the mother reported that the infant took only 2 ounces of formula every 3 hours. At the 4-month visit, the patient was taking about 4 to 5 ounces of formula every 3 hours and had not started juice or other solid foods. However, the mother mentioned that the infant took about an hour to finish each bottle with some increased effort and grunting, but no distress or hypoxia. There was no history of coughing with feeding, vomiting, diarrhea, or gastroesophageal reflux.
Developmentally, the patient smiled responsively, regarded her hands, followed past midline, cooed and looked to voice, but did not laugh or turn to voice. Also, she was not yet lifting her head to 45 degrees, bearing weight on her legs, or rolling over.
The physical exam was remarkable for a quiet infant in no apparent distress. Her vital signs were normal, and her weight was 4.22 kg, putting her in the 0.04 percentile for age. Her head circumference and length were in the 50th and 30th percentiles, respectively. She preferred laying on her right side, and her head was elongated posteriorly with bilateral temporal flattening (dolichocephaly). She had hypoplastic labia minora and clitoris, and her skin was slightly mottled in the lower extremities without any areas of hypopigmentation. Neurologically, she was limp and had significant head lag, a poor grasp reflex, and sluggish movement of her extremities. She was admitted for further evaluation.
The patient had both failure to thrive (FTT) and hypotonia. Although each may occur independently, each also can adversely affect the other. It can be challenging to know how much testing will be required to determine the primary cause. However, approximately 70% of cases of FTT are nonorganic (psychosocial) and are without a medical etiology (Table 1).
Nonorganic factors of FTT
Inadequate intake is usually explained by neglect, errors in formula preparation, inappropriate food for age, or errors in feeding technique. Contributing factors to these problems include socioeconomic status, lack of proper instruction, or psychosocial concerns such as postpartum depression.1 Although the patient’s mother had an adequate supply of formula and was in the process of enrolling for the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), inadequate food intake is the most common nonorganic cause of FTT.
A thorough diet and social history are crucial as poverty and inadequate access to food are the greatest single risk factors for FTT in both developed and underdeveloped countries.1,2 A nutritional history may uncover improper formula preparation or use, infrequent feeding, or early/late transition to other liquids or solid foods and can be clues for insufficient caloric intake.2 It is well known that some families may dilute the formula to make it stretch to the end of the month or the next paycheck.
Although this patient’s hypotonia was the more significant part of her presentation, given her stable condition, the decision was made to do a trial of ad lib feeding with calorie count and monitoring strict intake and output before proceeding down the workup for organic etiologies. She was given unlimited access to the same formula and gained less than an ounce a day over the course of the week. As the week progressed, organic causes became more likely and further investigations were begun.
Organic factors of FTT
The remaining 30% of FTT cases are organic and can be explained by an underlying medical condition (Table 1). Organic causes are numerous and can be associated with almost any organ system. A thorough history and physical examination should direct the laboratory and radiologic testing, and newborn screening results should be reviewed.
For respiratory or gastrointestinal causes, coughing with feeding can be present. It can be a sign of poor swallowing, aspiration, or gastroesophageal reflux. Although the patient had neither symptom, she took a long time to finish her bottle, possibly signaling an organic cause. Gastrointestinal causes such as gastroesophageal reflux, diarrhea, or malabsorption can lead to FTT.1
Endocrine disorders such as hyperthyroidism and hypothyroidism lead to an increased metabolic demand and result in poor weight gain.3 The patient’s first and second newborn screening results, including thyroid tests, were normal. Chronic diseases or infections, malignancy, or autoimmune conditions lead to increased energy demands and also can present as FTT (sometimes termed “anorexia of chronic disease”).4
Metabolic disorders such as fatty acid disorders, amino acid disorders, and enzyme deficiencies can lead to inadequate absorption or utilization of nutrients.5 These disorders represent about 5% of cases of infantile FTT, and newborn state screening programs have been successful in detecting many of these errors.
Chromosomal disorders are also associated with FTT because structural deformities or systemic pathologies can prevent adequate intake.6 Clues for these organic causes of FTT include systemic disease, multiorgan involvement, and family history of congenital disorders.5,6 Although the patient’s family history was noncontributory, the presence of hypotonia and developmental delay prompted further evaluation.
The differential diagnosis of hypotonia is extensive. Generalized hypotonia and developmental delay are common signs of many neuromuscular diseases presenting in infancy. These may also include neurologic disease, endocrine and systemic metabolic diseases, and a number of syndromes, or they may be nonspecific neuromuscular expressions of malnutrition (ie, FTT) or chronic systemic illness (Table 27).
Because of the infant’s prolonged feeding times, a swallow study was performed. Penetration (passage of contrast materials into the larynx but not through the vocal cords) was noted in the side position with the nectar consistency, and aspiration (passage of contrast materials below the true vocal cords) was noted in the sitting up position with all consistencies. The results were consistent with a diagnosis of pharyngoesophageal dysphagia.
Because of the patient’s abnormal genitalia, a chromosomal microarray analysis (CMA) was performed. Results showed a class II deletion in the Angelman syndrome (AS)/Prader-Willi syndrome (PWS) critical region on the proximal long arm of chromosome 15-a finding consistent with either of the 2 conditions. Molecular methylation studies were then recommended in order to differentiate between the 2 disorders. A Southern blot analysis of DNA from the patient utilizing a probe from the AS/PWS critical region revealed a single band of 4.0 Kb, the methylated maternally derived allele, but absence of the paternally derived nonmethylated band at 0.9Kb.
Magnetic resonance imaging (MRI) of the brain with and without contrast was performed and showed a mild paucity of T1-weighted myelin signal in the anterior limbs of the internal capsule and the deep occipital white matter. This suggested delayed or hypomyelination. There also was substantial right parietal, occipital, and left frontal plagiocephaly and mild hypoplasia of the inferior cerebellar vermis.
This patient’s FTT, developmental delay, hypotonia, abnormal swallow study, hypomyelination on the MRI, and a chromosomal microarray with a deletion in the critical region of chromosome 15 suggested either AS or PWS.
Although both AS and PWS have distinct phenotypes later in childhood, their diagnosis in infancy is difficult.8-10 The prevalence of both disorders is similar-about 1 in 10,000-and approximately 20,000 individuals in the United States are affected with each disorder. The following features may raise suspicion for these syndromes and prompt further testing.
Typically, patients with AS have a normal prenatal and birth history, and clinical diagnosis is not considered until after age 1 year.9 Diagnostic clues within the first year of life include hypotonia; feeding difficulties; severe developmental delay with delayed forward progression but no loss of skills; disproportionate growth in head circumference; and seizures with an abnormal electroencephalogram (EEG) pattern. Many of the classically associated signs of AS, such as an easily excitable, happy demeanor with inappropriate and frequent laughter, impaired verbal communication, and ataxic gait are only obvious in older children, making early recognition and diagnosis difficult.9,10
Like AS, PWS is rarely recognized within the first year of life.8-10 There are many different features exhibited in children with PWS, however, the characteristics that are most commonly associated with PWS do not manifest until later in life. The first clue to a diagnosis may be a history of decreased in-utero movement.8,11-14 Recently, there have been several reported cases of PWS being diagnosed in utero based on characteristic ultrasound findings, including decreased fetal movement, polyhydramnios, breech positioning, abnormal growth patterns, and malpositioned hands and feet.14 This constellation of findings on prenatal ultrasound, or any history of decreased fetal movements, warrants further analysis.
Children with PWS exhibit severe hypotonia, feeding problems with FTT, characteristic facial features (such as dolichocephaly, narrow face, almond-shaped eyes, and a small mouth), hypogonadism, and global developmental delay.8,11-13 As they get older, many children with PWS also exhibit temper tantrums and stubborn, compulsive behaviors.13,15 Commonly, children with PWS also have been noted to have a short stature attributed to growth hormone deficiencies. The most stereotypical features of PWS are hyperphagia and food-seeking behavior leading to rapid weight gain and obesity, usually beginning between ages 6 months and 6 years.8,11-15 Because of this later onset, these features are typically not helpful in making a diagnosis before age 1 year.
The main indicator of PWS in children aged younger than 1 year is severe hypotonia and FTT, as these are almost universal findings.8,11-15 These findings, along with a characteristic fetal history, should prompt further workup. A chromosome 5q11-13 deletion, seen via DNA analysis, is diagnostic of PWS.11
The patient in this case exhibited all the major criteria for a diagnosis of Prader-Willi syndrome: FTT with feeding difficulty, developmental delay, dolichocephaly, hypotonia, and hypogonadism. On swallow study, she was found to have feeding difficulties, specifically pharyngoesophageal dysphagia. The Southern blot analysis revealed a single methylated band of maternally derived DNA and the absence of paternally derived material. This restriction pattern was consistent with the diagnosis of PWS.
Because of the patient’s feeding difficulty, a nasogastric tube (NG) was placed. She was discharged home after 6 days and was referred to an academic center with a PWS clinic. Regular visits to her pediatrician for weight checks were recommended. Outpatient physical and occupational therapy were started with the goal of improving her strength and developmental milestones. Because of her abnormal swallow study, speech therapy was also ordered.
At her 6-month well-child checkup, the patient weighs 5.5 kg, still less than the 3rd percentile, and tolerates NG feeds well. The mother is going to start solid feeds as tolerated with management from speech therapy. The NG tube will remain in place for supplementation until feeding by mouth is completely tolerated and the infant shows consistent, appropriate weight gain.
Infants who fail to regain their birthweight by 2 weeks of age are concerning. This case underscores the importance of reviewing growth curves at every single clinic visit. When both FTT and hypotonia are present, further investigation is warranted. A careful history, including a detailed evaluation of social factors and feeding habits, a thorough physical examination, a review of the newborn’s state screening results, and additional tests as needed can help differentiate between acquired and congenital disorders.
Because both AS and PWS have unique features that only present later in childhood, clinicians need to be able to recognize nonspecific clues such as FTT, hypotonia, and developmental delay. Early diagnosis allows prompt medical intervention and enables parents to obtain helpful education and support.
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Mr Gupta is a medical student at the University of Texas Health Science Center at Houston (UTHealth), McGovern Medical School, Houston, Texas. Mr. Podolnick is a medical student, UTHealth McGovern Medical School, Houston. Dr Mazur is professor of Pediatrics, Department of Pediatrics, UTHealth McGovern Medical School, Houston. The authors have nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.