10 Going on 2: A Case of Short Stature in an Immigrant Child

An 11-year-old girl who recently moved to the United States from Guatemala presents with mild rhinorrhea. Per history, the child is healthy and has no medical issues except for difficulties with learning. However, per the mother’s report, she has never seen a doctor before today, either in Guatemala or in the United States. No health evaluation of the child was done when the child moved to the United States from Guatemala, and any documentation of immunization or newborn screen is unknown.The child was born at full term via cesarean section for breech presentation, with no prenatal or postnatal complications. However, her mother did not receive prenatal care before delivery. Her birth weight was 3.74 kg. During early childhood, her diet remained limited to canned foods and tortillas due to a lack of financial resources.On physical examination, her vital signs are within normal ranges for age. Her height is 80 cm, which is 9.5 SDs below the mean for her age. Her height age is 2 years old. Her weight is 13.5 kg, which is 6.9 SDs below the mean. As a result, her body mass index is in the overweight category at the 92nd percentile, which is inconsistent with her history of poor appetite and insufficient caloric intake. The child has no clinical evidence of puberty. She is in a stroller meant for a toddler and is nonambulatory. She has coarse facies, a hoarse cry, an enlarged tongue, thick skin, and a protruding abdomen with a small reducible umbilical hernia. She does not have hepatosplenomegaly and has no apparent bony deformities (Figure 1). When asked, her mother mentions that the child’s paternal aunt looks like her. Her speech and development are consistent with that of a 2-year-old child.Given her short stature, coarse facies, and umbilical hernia, both mucopolysaccharidosis (MPS) and hypothyroidism are suspected. Thyroid-stimulating hormone (TSH) and free thyroxine (T4) are sent for laboratory results, and referrals are placed for medical genetics and endocrinology concurrently. Medical genetics is notably impressed by the clinical presentation and prioritizes the patient for an urgent evaluation, which includes urine testing for MPS disorders. Endocrinology provides preliminary recommendations while awaiting an appointment.Abdominal ultrasound is unremarkable. Skeletal radiographs reveal normal cervical spine, scoliosis to 15 degrees, widening of the femoral necks bilaterally, and mild widening of the long bones of the bilateral lower extremities. Her echocardiogram is normal. She has an estimated skeletal age of 4 years based on Greulich and Pyle’s reference standards.1 Serum chemistry is nondiagnostic; she has only a mild elevation in liver enzymes. Other tests are pending to confirm the diagnosis.Due to viral symptoms on day of presentation, family declines catch-up vaccines. However, on subsequent visits, she is completely caught up on her immunizations.Testing for urinary mucopolysaccharides is positive, but subsequent confirmatory genetic tests, including the Invitae Mucopolysaccharidoses Plus Panel,2 are negative. Significant elevation of the TSH to 708 uIU/mL, along with a low free T4 level (<0.4 ng/dL, FT4), confirms a diagnosis of severe primary (likely congenital) hypothyroidism. A thyroid ultrasound is performed to determine the etiology of hypothyroidism, which shows small and heterogeneous lobes without goiter.Unrecognized and untreated hypothyroidism within the first 2 to 3 years of life leads to severe short stature and intellectual disability (Figures 2 and 3). Thyroid hormone (TH) is paramount for normal brain development and bone growth, especially in the first few years of life. Prompt diagnosis and management, thanks to universal newborn screening (NBS) in the developed world, has almost eradicated the profound detrimental effects of TH deficiency on growth and neurodevelopmental outcomes (cretinism). However, unrecognized congenital hypothyroidism (CH) continues to be a leading cause of preventable intellectual disability globally.3 As many as 70% of infants worldwide are born in areas that do not have access to NBS.4 A small percentage of parents within the United States continue to refuse NBS.5 Also, a delayed postnatal TSH surge, as commonly seen in premature infants, can result in a missed diagnosis if NBS is only collected within the first day or two of life.6,7 Thus, it is important for pediatricians to maintain familiarity with the clinical presentation of untreated CH.The incidence of primary CH is between 1 in 3000 and 1 in 2000, with the most common cause in North America being sporadic failure of normal thyroid gland development (thyroid dysgenesis). Globally, severe maternal or infant iodine deficiency is the most frequently seen pathology.8 Our patient comes from Guatemala, where iodine intake has recently improved in the general population. However, with a severely nutrient-limited diet described by the patient’s mother, iodine deficiency remains a culpable contributor. Given her clinical presentation with severe short stature and developmental delay, we suspect that the onset of hypothyroidism was either congenital or within the first 2 to 3 years of life. Because her paternal aunt has a similar history, genetic causes leading to dyshormonogenesis are also possible (2%–5% of CH cases).9 We did not pursue further genetic testing to screen for genetic etiologies of CH in our patient because it would not have led to a change in clinical management. Thyroid ultrasound was pursued and revealed a small, underdeveloped thyroid gland, which could potentially suggest thyroid dysgenesis, the most common etiology of CH.The clinical signs and symptoms of hypothyroidism can be nonspecific and generalized due to the multifaceted role of TH in the body (Table 1). The role of TH in neurodevelopment and growth is illustrated by the significant short stature and global developmental delay noted in our patient. Low metabolism and increased systemic vascular resistance secondary to severe hypothyroidism can lead to bradycardia, hypothermia, myxedema, and increased weight gain despite poor appetite. Low muscle tone is responsible for the inability to bear weight, protuberant abdomen, umbilical hernia, and appearance of macroglossia. Constipation, coarse skin and hair, delayed dentition, poor feeding, and poor dentition were other characteristic symptoms elicited on further evaluation. Delayed bone development can result in wide-open fontanelles, delayed dentition, and delayed bone age. Direct hyperbilirubinemia due to the role of TH in maintaining bile flow is often noted in infants with untreated CH. The mild aspartate aminotransferase and alanine aminotransferase elevation seen in our patient can also be explained by myopathy caused by T4 deficiency.10TH also plays a crucial role in the onset of puberty, and untreated hypothyroidism can be associated with a delayed onset of puberty. Following this pattern, our patient presented aged 11 years with no clinical signs or biochemical evidence of puberty. However, there are cases in which hypothyroidism can actually lead to precocious puberty. Van-Wyk-Grumbach syndrome is a reported clinical entity seen with severe primary hypothyroidism in which the significantly elevated level of TSH is speculated to directly stimulate the FSH receptor and lead to the early onset of puberty despite a delayed bone age.In the presence of clinical suspicion, a significant TSH elevation with a low or normal FT4 level can help establish the diagnosis of primary hypothyroidism. Once confirmed, treatment should be started with oral daily levothyroxine as soon as possible, regardless of the etiology of hypothyroidism. Treatment for CH should ideally be initiated within 2 weeks of age to achieve normal cognitive development. The initial starting dose of levothyroxine in infants is 10 to 15 μg/kg/d, whereas older children with primary hypothyroidism are usually started on 2 to 4 μg/kg/d. In comparison, adults are typically started on levothyroxine 1 to 2 μg/kg/d. Dosing is titrated over time to maintain TSH within a normal age-appropriate reference range. With profound hypothyroidism, as seen in our case, abrupt initiation of maximal dose replacement therapy can precipitate fatal arrhythmias, myocardial infarction events, or pseudotumor cerebri.11,12 Therefore, the usual approach is to start with a lower dose of levothyroxine and gradually titrate to a euthyroid state.Interestingly, an MPS disorder such as Hurler syndrome was first suspected upon visualization of the patient. Despite being a lysosomal storage disease with vastly different pathogenesis, Hurler syndrome can mimic untreated CH. Both untreated CH and Hurler syndrome present with short stature and developmental delay. Both can also present with coarsening of or changes to facial features and umbilical hernias, as seen in our patient.13 Some features typical of Hurler syndrome not noted in our patient include corneal clouding, organomegaly, hirsutism, and cardiac abnormalities.14Our patient is started on a levothyroxine dose of 1 μg/kg/d initially. The dose is gradually uptitrated to 3 μg/kg/d. The family has some initial struggles with adherence to the dosing regimen, including language barrier, uncertainty with transportation for picking up the medication, issues navigating our health care system for refills, and remembering to take the medication every day. However, after several clinic visits and with patient education, the family is able to consistently administer the medication. Her thyroid function test results are now within age-based reference ranges on this dose. After a year on levothyroxine, we have noticed a drastic improvement in her clinical appearance, symptoms, growth, and neurodevelopmental state. She attained thelarche at a chronologic age of 12 years despite having a concurrent delayed bone age of 6 years.SummaryClinical presentations may mimic one another, so it is important to maintain a broad differential diagnosis on initial evaluation.Untreated CH is rare in the United States but can still be seen.Maintain some level of suspicion when confronted with a child who is not meeting growth or developmental milestones, especially (but not just) in those who may not have had an appropriately drawn, US newborn screen.Globally, iodine insufficiency is the leading cause of CH, with genetic causes being much less common.When starting levothyroxine for profound long-standing hypothyroidism, start at a lower dose and titrate up to the weight-based goal slowly to avoid potentially fatal arrhythmias and/or myocardial infarction events that can result from sudden exposure to a normal amount of TH.We are grateful to the patient’s family for allowing us to share her case with the readers of this vignette.