Congenital Hypothyroidism Presenting with Myxedema Coma

1. Congenital Hypothyroidism Presenting with Myxedema Coma Christine Kim, MD1, Robyn Kuroki, MD2 1Department of Internal Medicine-Pediatrics 2Department of Pediatrics Los Angeles County + University of Southern California Medical Center

2. ID: 36 y/o female from Guadalajara with untreated congenital hypothyroidismCC: Respiratory distress History of Present Illness: • 1 week PTA: Congestion and nasal discharge causing decreased sleep x 3 days • Outside clinic: IM injection of antibiotic x3 days, given 5 days of Azithromycin along with Albuterol syrup, phenergan, prednisolone and Tylenol • DOA: Worsening congestion and difficulty swallowing, Episodes of perioral cyanosis lasting 3 min • ROS: no fevers, +constipation (daily suppositories), +night-time snoring, + dry skin, decreased activity level from baseline

3. Development @ Baseline • Social (~12 mo): work for toy, play pat-a-cake, indicate wants, waves bye-bye, rolls ball with examiner • Language (expressive ~6mo; receptive ~10mo): nods/shakes her head, hand gestures • Fine Motor (~6 mo): raking grasp, pass cube, take 2 cubes • Gross Motor (~10 mo): crawls, sits up by herself, walks with both hands being held and supported, turns pages of books, not toilet trained

4. Physical Exam Vital signs BP: 123/72, HR: 63, RR: 12, , T 97.8, Pain: 0/10   Weight: 16.5 kg Height: 81 cm BMI: 25.1 kg/m2 HC: 51cm GENERAL: very small for stated age , coarse facial features, appearing about 2-3 years old, non-verbal HEENT: large anterior fontanelle open and flat, deep set nose, large dry lips, large thick partially visible tongue, poor dentition, coarse/sparse hair, (frenulum attached) NECK: thick neck, no palpable goiter or thyroid nodules, + shotty cervical LAD CHEST: coarse breath sounds b/l, no wheeze/retractions, no stridor, SMR (B) 1 CARDIAC: S1 +S2, regular rhythm, heart rate 50-60’s no murmurs/gallops/rubs ABD: protuberant abdomen, small umbilical hernia, soft, nontender no HSM GU: SMR 1 female EXT: short fingers and toes, short arms and legs, broad edematous hands b/l NEURO: deep tendon reflexes hypereflexic with markedly delayed return phase SKIN: pale, dry boggy skin, with myxedematous changes, multiple nevi with raised nevi at external ear canal on left

5. In the hospital

7. Labs 99.7 Ca 10.6 Phos 2.4 Mg 1.9 109 145 14 7.1 268 250 8.2 3.5 22 0.7 21.2 14.8 N77 L19 M4 B0.1 CK 87 LDH 215 PT 16.4s INR 1.31 PTT 20.3s Lactate 4.3 Ammonia 32 CRP 5.3 0.2 6.5 35 58 3.3 24 0.1 VBG: pH 7.3 pCO250 pO2 45 HCO3 25 BD 1.1 O2 75%

8. AM Cortisol 17.6 LH <1.0 FSH 2.1 Estradiol 21 DHEAS 23 GH 0.8 IGF-1 <25 Vit D 25-OH 11 Endocrine Labs • TSH 208 • FT4 <0.4 • FT3 <1.1 • Thyroglobulin 4.2 • Thyroglobulin Ab <1 • PTH 66 • Prolactin 113.4

9. CXR/KUB • Cardiomegaly • Increased interstitial markings • Distended stomach • Immature skeleton

10. Widened sutures Wormian bones Skeletal Survey

11. Flattening of bodies Thoraco-lumbar kyphosis SkeletalSurvey

12. Cretinoid epiphyseal dysgenesis • Shortening of long bones

13. Carpal bone age ~3 yrs Distal bones ~1yr 3mo Bone Age

14. MRI Brain • Mildly prominent pituitary gland • No sellar mass

15. Studies Echo: decreased ejection fraction, mild aortic insufficiency, heart walls that appear to have myxedematous changes Thyroid U/S: no evidence of thyroid tissue within neck

16. Learning Objectives • Review Congenital Hypothyroidism • Know about the uncertainties in managing adults with congenital hypothyroidism who have never been treated before

17. Congenital Hypothyroidism • Thyroid hormone deficiency at birth • Most common treatable causes of mental retardation • Screening: newborn screening since mid-1970’s • Incidence • 1: 4,000-3,000 newborns • Hispanic, American Indian/Alaska Native people (1:2,000-700 newborns) • Black 1:3,200-17,000

18. Etiology • Common form of thyroid dysgenesis • Aplasia • Hypoplasia • Ectopic gland (66%) • Cause of thyroid dysgenesis is unknown (85% sporadic, 15% hereditary) • Mutations • Inborn errors of T4 synthesis, secretion, or utilization (2/3 heritable cases) • Transient Hypothyroidism • Maternal Autoimmune thyroiditis • Maternal medication for Graves’ disease • Endemic cretinism from iodine deficiency

19. Screening • Started in Mid-1970’s • Measure T4 & TSH > 48 hrs of life • T4 – false-positive rate 0.30% • TSH – false-positive 0.05% • Preterm infants have higher false-positive • Not affected by diet or transfusion; but total exchange transfusion • If +  confirm  thyroid US or thyroid uptake scan • If maternal autoimmune thyroid disease  measure TSH-binding inhibitor Ig • If iodine exposure/deficiency  measure urinary iodine

20. Clinical Manifestations Infants protected for 1st few wks of life • Fraction of maternal thyroid hormone crosses placenta • >40 wk GA • HC Slightly higher % due to brain myxedema • Large fontanels & wide sutures • Macroglossia • Distended abdomen with umbilical hernia • Skin mottling • Goiters (5-10%) • Sensorineural deafness (10%) • Other congenital anomalies (10%) • Slow to feed • Constipation • Lethargic • Sleep more, needs to be awakened to feed • Hoarse cry • Cool to touch • Hypotonic with slow reflexes • Prolonged jaundice

21. If undiagnosed at a later age… • Slow linear growth • Loss of IQ • Ataxia • Gross/fine motor incoordination • Hypotonia & spasticity • Speech disorders • Attention deficit • Strabismus • Sensoriuneural deafness (10%)

22. Disease Management • Levothyroxine (~10-15 m/kg/day) • Goal: T4 1.2-2.3 ng/dL TSH <6 mU/L • Monitor T4 & TSH @ • 2 & 4 wks after treatment • q1-2 months in 1st year • q3-4months between 1-3 yrs • 2-4wks after any change in dosage

23. Myxedema Coma • Myxedema coma is a medical emergency, typically caused by a precipitating event in a patient with chronically untreated hypothyroidism

24. To treat, or not to treat….For in this unique case Pros to therapy Cons to therapy Menses Increased caretaking responsibilities Increased medical monitoring Behavioral changes (aggressiveness, mood liability) • Developmental or maturational changes • Increased social interactions • Prevent myxedema coma • Prevent hospitalizations • Compatible with life/sustains life

25. Case report cont. Prior to Therapy 7 months after therapy

26. References • Boersma, B., et al. Catch-up Growth after Prolonged Hypothyroidism. Eur J Pediatr. 1996. 155:362-367. • Congenital Hypothyroidism, Nongoitrous,2. Centre for Arab Genomic Studies • Dubuis, J., et al. Outcome of Severe Congenital Hypothyroidism: Closing the Developmental Gap with Early High Dose Levothyroxine Treatment. J of Clinical Endo and Met. 1996. 81(1):222-227. • Eberle, Andrea. Congenital Hypothyroidism Presenting as Apparent Spondyloepiphyseal Dysplasia. Am Journ of Med Genetics. 1993. 47:464-467. • Hirayama, T., et al. The Longitudinal Course of Two Cases with Cretinism Diagnosed After Adolescence. J. Nippon Med Sch 2003. 70(2):175-178. • Ishikawa, N. et al. A Case of Turner Syndrome with Congenital Hypothyroidism Untreated until Age 38 Years. Horm Res. 2003. 59:50-54. • Kaye, C. & Committee on Genetics. Newborn Screening Fact Sheets. Pediatrics 2006. 118:e934-e963. • Meyers D, Haering S. Screening for Congenital Hypothyroidism in Newborns:A Literature Update for the U.S. Preventive Services Task Force. AHRQ Publication No. 08-05109-EF-1. Rockville, MD: Agency for Healthcare Research and Quality, 2008. • Oerbeck, B., et al. Congenital Hypothyroidism: Influence of Disease Severity and L-Thyroxine Treatment on Intellectual, Motor, and School-Associated Outcomes in Young Adults. Pediatrics Oct 2003. 112 (4):923-930. • Rose, S., Brown, R. Update of Newborn Screening and Therapy for Congenital Hypothyroidism. Pediatrics. June 2006. 117(6):2291-2303.

27. Question • A 13 year-old diagnosed with congenital hypothyroidism was brought in by mother after missing appointments for >1 yr. Physical examination reveals length at the 5th percentile, weight at the 10th percentile, dry skin, and non pitting edema in bilateral lower extremities. Mother also concerned with constipation. You order TSH and FT4 and increase the thyroid hormone replacement therapy from 50mcg to 100mcg.

28. Question Of the following, the MOST likely long-term outcome in this child: • Adrenal Insufficiency • Diabetes mellitus • Learning disorder • Normal adult height • Precocious puberty

29. Answer - C • Children who have severe hypothyroidism at birth tend to have poorer intellectual outcomes than their siblings, even if therapy is started in the first few days after birth • With continued and appropriate thyroid hormone therapy, this child should grow normally in height, and adult height should be appropriate for the family. However, this child has been chronically undertreated for many months. • Congenital hypothyroidism is not associated with adrenal insufficiency, although acquired hypothyroidism because of chronic lymphocytic thyroiditis may be associated with the development of autoimmune adrenal insufficiency (Addison disease). • Precocious puberty is not an outcome of congenital hypothyroidism unless a child is overtreated with thyroid hormone and develops premature maturation, which is very unusual. Some children who have severe acquired hypothyroidism have manifested signs of sexual precocity that disappear after treatment of the hypothyroidism (Van Wyk-Grumbach syndrome).