Diagnostic Dilemma: A 3-Year Old Boy with Global Developmental Delay, Truncal Hypotonia, Peripheral Hypertonia, and Central Hypothyroidism

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 414-431-HPT Axis Biology
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-430
Amy Levenson*, Wen-Hann Tan and Stephen A. Huang
Boston Children's Hospital, Boston, MA
Introduction:  Allan-Herndon-Dudley syndrome (AHDS) is an X-linked recessive disorder characterized by congenital hypotonia and intellectual disability, with limited motor and language skills.  Affected children are hypertriiodothyronemic, with variable serum TSH and T4 concentrations.  Recent research has revealed that loss of function mutations in the SLC16A2 (MCT8) gene on chromosome Xq13.2, which encodes the neuronal triiodothyronine transporter monocarboxylate transporter-8 (MCT8), are a major cause of AHDS.              

Clinical Case:  A 22 month old boy with a history of severe global developmental delay, hypotonia, and feeding intolerance, was referred to our endocrine program for consultation.  At the time of evaluation, the patient was receiving levothyroxine therapy for presumed central hypothyroidism, based upon the documentation of characteristic serum thyroid function tests at 13 months of age:  TSH 3.97 µU/mL (normal 0.35 to 5.5) with free T4 0.69 ng/dL (normal 0.8 to 1.8).  His physical examination was notable for bitemporal narrowing, tall forehead, deeply set eyes, horizontal nystagmus, anteverted nares, truncal hypotonia with head lag, and peripheral hypertonia.  Brain MRI showed no pituitary abnormalities, but noted unmyelinated white matter within the subcortical regions of the frontal and temporal lobes, delayed for age.  Review of serial thyroid function tests showed persistent hypothyroxinemia (serum free T4 0.64 to 0.72 ng/dl) with inappropriately low or normal serum TSH concentrations (TSH 0.262 to 4.15 µU/mL), despite levothyroxine doses as high as 100 mcg (8 mcg/kg) daily.

As these features suggested the possibility of AHDS, we measured serum T3 and documented hypertriiodothyronemia (total T3 318 ng/dL, normal 94 to 241).  Genetics was consulted and the patient was tested for mutations in SLC16A2, which revealed an unreported c.825C>A (p.Y275X) nonsense mutation, confirming the diagnosis of AHDS.  We discontinued levothyroxine, and repeat serum tests six months later showed TSH 2.55 µU/mL, free T4 0.72 ng/dL, THBR 0.92, and total T3 293 ng/dL.  Genetic testing of the patient’s mother and maternal grandmother is underway. 

Conclusions:  We describe a previously unreported SLC16A2 mutation c.825C>A (p.Y275X) as a cause of human MCT8 deficiency and AHDS.  This patient’s phenotype matches that of other individuals with AHDS, as described in the literature.  His presentation illustrates the diagnostic challenges of AHDS and the importance of maintaining an appropriate index of suspicion in children who have neurodevelopmental delay of unknown cause.  As researchers have recently reported encouraging results with thyromimetics, such DITPA and Tetrac, in MCT8-deficient mice and even humans, there is great optimism that timely diagnosis of affected individuals will permit the benefit of individual therapy as well as genetic counseling.

(1) Schwartz CE et al., Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):307-21. (2) Visser WE et al., Clin Endocrinol (Oxf). 2013 Feb;78(2):310-5. (3) Verge CF et al., J Clin Endocrinol Metab. 2012 Dec;97(12):4515-23. (4) Horn S et al., Endocrinology. 2013 Feb;154(2):968-79.

Nothing to Disclose: AL, WHT, SAH

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm