Molly O. Regelmann

Down Syndrome and Thyroid Function

Thyroid dysfunction in children with Down syndrome (DS) can occur as early as birth. As children with DS age, their risk for thyroid autoimmunity manifested as autoimmune hypothyroidism or Graves disease increases. The optimal timing and method for thyroid screening in children with DS remains controversial. The American Academy of Pediatrics recommends annual screening in this population. Consensus is needed to establish working definitions of euthyroidism and mild hypothyroidism in all infants, but especially in those with DS.

Update on Turner and Noonan Syndromes

Turner syndrome (TS) and Noonan syndrome (NS) have short stature as a constant feature; however, both conditions can present clinicians with a challenging array of genetic, cardiovascular, developmental, and psychosocial issues. In recent years, important advances have been achieved in each of these areas. This article reviews these two syndromes and provides updates on recent developments in diagnostic evaluation, growth and development, psychological issues, and treatment options for patients with TS and NS.

Endocrine Dysfunction in X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene and leads to an elevation of very-long-chain fatty acids (VLCFA). The accumulation of the VLCFA and the associated oxidative stress can present with a spectrum of significant neurologic disease, adrenal insufficiency, and testicular dysfunction in males with ABCD1 gene mutations. Much of the published literature for X-ALD has focused on the associated devastating progressive neurologic conditions. The purpose of this review is to summarize the concerns for endocrine dysfunction associated with X-ALD and provide guidance for monitoring and management of adrenal insufficiency.

Small at Birth, but How Small? The Definition of SGA Revisited

50 years of published discussion of the definition of SGA [3–5] . The 10th percentile was chosen as a cutoff for SGA in the 1960s as a result of multiple studies indicating that infants born at or below the 10th percentile have increased mortality compared to gestational age-matched controls [4] . It is worth noting that these studies were performed on neonates born at high altitudes, who tend to be smaller compared to those born at sea level [4, 5] . Defining SGA as 2 SDs below the mean was also suggested in the 1960s, as it would only define 4.6% of births as abnormal (approximately 2.3% SGA and 2.3% large for gestational age), as opposed to 20% (10% SGA and 10% large for gestational age). Additionally, the 2 SD cutoff roughly corresponded with an earlier study reporting that 2.3% of neonates were born at 25% below the mean weight when controlled for gestational age [5] . In 1995, the World Health Organization published recommendations defining SGA as less than the 10th percentile of weight for gestational age using localized anthropometric newborn curves [3] . In 2007, a consensus meeting that included representatives from seven international pediatric endocrinology societies, as well as a representation from obstetrics, perinatology and neonatology, pediatrics, epidemiology, and pharmacology, recommended that SGA be defined as more than 2 SDs below the mean for weight and/or length [2] . They also recBeing born small has been associated with many shortand long-term health sequelae. Perinatally, it is associated with increased mortality, lung disease, hypotension, necrotizing enterocolitis, poor thermoregulation, hypoglycemia, and polycythemia [1, 2] . Long-term, small infants are at risk for insulin resistance, type II diabetes mellitus, cardiovascular disease, chronic kidney disease, neurodevelopmental and cognitive impairments, developmental delays, behavioral problems, and adult short stature [1] . But how ‘small’ is ‘too small’? The term ‘small for gestational age’ (SGA) describes newborns who have lowerthan-expected weight, length, and/or head circumference when controlled for gestational age and sex. This is different from intrauterine growth retardation, which refers to poor growth in utero evidenced by at least two ultrasound measurements [2] , and prematurity, which is a broad term defining neonates born prior to 37 weeks gestation. Some, but not all, infants with intrauterine growth retardation and/or prematurity may be born SGA. In spite of potential significant health implications, the exact definition of SGA remains elusive. Multiple criteria have been used, including less than the 10th, 5th, and 3rd percentile in weight, length, or head circumference. Another definition of SGA is parameters more than 2 standard deviations (SDs) below the mean, or the 2.3rd percentile [1, 2] . These discrepancies are not novel, with over Received: August 11, 2016 Accepted: August 12, 2016 Published online: September 30, 2016 HORMONE RESEARCH IN PÆDIATRICS

New-onset diabetes mellitus after pediatric liver transplantation

In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high‐risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy.

Thyroid "vise" in an infant with neonatal Graves' disease.

On the rare occasion when neonatal goiter is the cause of airway compromise, it typically presents with a palpable neck mass. In the setting of maternal Graves’ disease (GD), fetal and neonatal goiters are most commonly caused by maternal treatment with antithyroid medication, and the goiter resolves within days of initiation of thyroxine replacement in the neonate. We describe an atypical presentation of a patient with severe neonatal GD born to a euthyroid mother at 35 weeks’ gestational age with respiratory compromise, symptoms of hyperthyroidism, and a nonpalpable thyroid gland. The mother had a history of GD treated with radioactive iodine ablation; during the pregnancy she was treated with levothyroxine throughout and propylthiouracil beginning at 5 months’ gestation, for fetal tachycardia. Laboratory testing after birth confirmed neonatal GD. The patient was treated with methimazole, Lugol’s solution, and levothyroxine, and the patient remained euthyroid from day of life 10. After multiple extubation attempts failed, the patient was found on visualization studies to have a large, predominantly posterior, “vise-like” goiter encasing the larynx and upper trachea. The patient was successfully extubated, and all medications were discontinued on day of life 60. The patient remained euthyroid 1 month after discontinuation of treatment. The patient’s atypical presentation illustrates the need for early neck imaging in patients with neonatal GD and respiratory distress, especially when the thyroid gland is not palpable. Treatment options for resolving a goiter due to neonatal GD are not clear.

The role of ¹²³I imaging in the evaluation of infants with mild congenital hypothyroidism.

Background/Aims: Controversy exists regarding the diagnosis and treatment of mild congenital hypothyroidism (MCH). We studied the value of ¹²³I imaging in patients with MCH. Methods: Retrospective chart review of infants and children <4 years of age who underwent ¹²³I imaging: group 1 = MCH [thyroid-stimulating hormone (TSH) <25 µIU/ml, normal free T₄/T₃], group 2 = severe congenital hypothyroidism (TSH ≥25 µIU/ml), and group 3 = MCH in infancy imaged after treatment withdrawal at age 3 years. Data collected included 4- and 24-hour ¹²³I uptake, TSH, free T₄/total T₃ at imaging, age at imaging, and levothyroxine (<smlcap>L</smlcap>-T₄) dose at 1 year of. Results: Thirty-six patients underwent ¹²³I imaging. In group 1 (n = 20, median TSH: 8.49 µIU/ml), 85% had abnormal imaging consistent with dyshormonogenesis. Two patients were referred after 1 year of age. The median age at imaging for the remaining 18 patients was 54 days. Median <smlcap>L</smlcap>-T₄ dose at 1 year of age for these 18 patients was 2.8 μg/kg, which is consistent with dyshormonogenesis. Ninety-one percent of group 2 (n = 11, median TSH: 428.03 µIU/ml) had abnormal imaging. The median age at imaging was 13 days. Four patients in group 3 had abnormal ¹²³I imaging and restarted treatment. Conclusion:¹²³I imaging is a valuable tool for evaluation, diagnosis, and treatment of MCH.

Growth Hormone Treatment in Patients with Hypochondroplasia

plasia with developmental delay and acanthosis nigricans, achondroplasia, and HCH [4] . The most commonly found genotype for patients meeting clinical and radiographic criteria for HCH is the N540K mutation in the FGFR3 gene on chromosome 4p16.3. Adult heights for patients with the clinical diagnosis of HCH have been reported to vary widely: from 145 to 165 cm in males and from 133 to 151 cm in females [5] . The broad spectrum of adult height lost may be attributable to varying degrees of penetrance even among children with the same FGFR3 genotype [6, 7] . Reports of the benefits of recombinant human growth hormone (hGH) treatment in children with skeletal dysplasias are mixed. In children with achondroplasia, there may be transient improvement in height velocity without improvement in adult height. Thus, the use of hGH to treat achondroplasia is not routinely recommended [4] . For children with HCH, there are no reports of placebocontrolled trials that have evaluated the use of hGH treatment to adult height. Previous reports of patients with HCH suggested an improvement in height velocity when treated with hGH, particularly at the time of the pubertal growth spurt [5, 8] . A report of 6 children with the N540K mutation of the FGFR3 gene treated with growth hormone also showed improvement in height velocity and trunk/leg disproportion; however, the study lacked control patients for comparison and the patients were not followed up to adult heights [9] . In children evaluated for short stature or growth failure, subtle skeletal dysplasias may be difficult to identify, particularly before puberty when skeletal disproportions are less obvious. Children with mild forms of skeletal dysplasias, including hypochondroplasia (HCH), may be mislabeled as having ‘growth failure of unknown etiology’, otherwise known as ‘idiopathic short stature’ [1] . Patients with HCH have also been labeled as ‘small for gestational age’ or having ‘familial short stature’ [2] . Stimulation testing has occasionally been performed in patients with HCH and some have been diagnosed with growth hormone deficiency that was not reproduced on subsequent testing [3] . Correctly identifying children with skeletal dysplasias is important to establish appropriate treatment regimens as well as manage expectations for short-term growth and adult height. The diagnosis of HCH can be established by clinical, radiographic, and genetic testing. Clinically, children with HCH may have short stature, an increased upper-to-lower segment ratio, short arm spans, and macrocephaly. Radiographic abnormalities include decreased interpedicular distances between lumbar vertebrae L1 and L5 and short lumbar pedicles in the absence of other gross radiographic abnormalities. FGFR3 mutations have been reported in subjects with skeletal dysplasias. The phenotype of affected individuals varies according to the FGFR3 mutation and ranges from thanatophoric dysplasia to severe achondroPublished online: December 16, 2014 HORMONE RESEARCH IN PÆDIATRICS

Thyroid Ultrasound: More Sensitive than Radioactive Iodine Imaging in Detecting Recurrence of Papillary Thyroid Cancer in Two Pediatric Patients

Background: Papillary thyroid cancer (PTC) is an uncommon pediatric disease with an excellent prognosis. In follow-up surveillance, neck ultrasound (US), basal and thyroid-stimulating hormone-stimulated serum thyroglobulin (Tg) levels, and diagnostic whole-body radioactive iodine scans (DxWBS) have been traditionally used in both adults and children for the detection of recurrence or metastases of PTC. Methods: Two pediatric patients with metastatic PTC were followed after standard ablative treatment with routine neck US and serum Tg levels, as well as periodic DxWBS. Results: Neck US identified recurrent and metastatic PTC which DxWBS failed to detect. Conclusion: Neck US was superior to DxWBS in the detection of recurrent PTC in these 2 pediatric patients. These findings are consistent with the 2015 American Thyroid Association (ATA) Guidelines that neck US is an ideal imaging modality in pediatric patients for the surveillance of PTC local recurrence or lymph node metastases.