Elsevier

European Journal of Medical Genetics

Volume 53, Issue 6, November–December 2010, Pages 392-395
European Journal of Medical Genetics

Short report
Allan–Herndon–Dudley syndrome (AHDS) caused by a novel SLC16A2 gene mutation showing severe neurologic features and unexpectedly low TRH-stimulated serum TSH

https://doi.org/10.1016/j.ejmg.2010.08.001Get rights and content

Abstract

Thyroid hormones are known to be essential for growth, development and metabolism. Recently mutations in the SLC16A2 gene coding for the monocarboxylate thyroid hormone transporter 8, MCT8, have been associated with Allan–Herndon–Dudley syndrome (AHDS), an X-linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia. Here we describe in detail the clinical and biochemical features in a boy affected by AHDS with severe neurological abnormalities and a novel de novo SLC16A2 gene insertion, 1343–1344insGCCC, resulting in a truncated protein lacking the last four transmembrane domains (TMDs) as well as the carboxyl cytoplasmic end. He presents mental retardation, axial hypotonia, hypertonia of arms and legs, paroxysmal dyskinesias, seizures. The endocrine phenotype showed low serum total and free thyroxine (T4), very elevated total and free triiodothyronine (T3) and normal thyrotropin (TSH) with blunted response to thyrotropin-releasing hormone (TRH). The latter finding was unexpected and suggested that the lack of functional MCT8 was counterbalanced at the thyrotrope cell level by high serum T3 concentration and/or by increased intrapituitary type 2 deiodinase (D2) activity. Our case constitutes a relevant contribution to better characterize this disorder and to elucidate the functional consequences of SLC16A2 gene mutations.

Introduction

Allan–Herndon–Dudley syndrome (AHDS; MIM 309600) is one of the first X-linked mental retardation (XLMR) syndromes reported [1] and among the first XLMR conditions to be genetically mapped [22]. Infancy and childhood in AHDS are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones [20]. Thyroid function tests show elevated T3 and decreased T4 levels in the presence of borderline-high thyrotropin (TSH) secretion.

Recently it was shown that mutations in the SLC16A2 gene, one of the most specific and active thyroid hormone transporters, MCT8, were detected in patients with AHDS [6], [9], [16], [17], [19], [20], [24]. Here we report a patient of Sardinian origin with a severe form of AHDS due to a novel insertion mutation in the SLC16A2 gene, associated with a peculiar thyroid hormone phenotype.

The patient, 5 years old, is the second child born to non-consanguineous, apparently healthy parents of Sardinian origin. There was no family history of psychomotor delay or thyroid disorder. The pregnancy was uneventful and delivery occurred at gestational age 40 weeks with a birth length of 50 cm (50%ile), weight of 3,030 gr (25%ile), and head circumference of 34 cm (25%ile), APGAR score 9–10. Neonatal thyroid screening was within the reference range (TSH <20 mU/L, normal reference range <20 mU/L) and the newborn was not reassessed, in spite of slightly decreased spot T4 concentration (5.8 μg/dl, normal reference range >6.0 μg/dl). The patient was noticed to have a hypotonia and at the age of 2 months he presented tremor, restlessness with crying and impairment of sleep pattern. The hypotonia progressed to spasticity by age of 6 months with hyperreflexia, Babinski, clonus and dystonic movements of face, neck and distal limbs. At present the boy, 5 years old (Table 1), shows height at 10th percentile, weight <3rd percentile and acquired microcephaly (head circumference <−2DS). He presents severe mental retardation, axial hypotonia and generalized weakness with difficulty in supporting the head, hypertonia of arms and legs. Physical examination shows low muscle and fat mass in spite of normocaloric alimentation, slightly myopathic facies and retrognathia, pectus excavatum, severe cervicodorsal and dorsolombar scoliosis, long and thin everted feet and an undescended left testicle. He is not able to sit, crawl or speak. He shows paroxysmal dyskinesias during the sleep: hyperextension of the neck, turning of the head, opening of the mouth, tonic stretching of the arms and leg and inconsolable crying, suddenly interrupted when the crisis stopped (Fig. 1). These episodic paroxysmal dyskinesias occur also when awake, spontaneously or provoked by passive movement of body or limb position. These attacks last each from less than a minute to several hours and occur up to 150 times per day. He also presents additional tonic clonic convulsions with upwards ocular deviation, opening of the mouth and laughter unresponsive to several cycles of anti-epilectic drugs like diazepam, carbamazepine, clobazam and nitrazepam. In addition he shows repeated episodes of pneumonia because of gastroesophageal reflux.

Laboratory examinations showed normal hematological and blood chemical values except for low levels of total cholesterol and HDL. No metabolic abnormalities were observed in blood, urine and liquor, muscular biopsy was normal and endocrine studies were normal except thyroid function with high serum total and free T3 levels, low reverse triiodothyronine (rT3), low total and free T4 levels, normal basal serum TSH and high serum sex hormone-binding globulin (SHBG) levels (Table 1). Thyroid ultrasound and thyroid scan was normal. Fundoscopic examination, abdominal ultrasound and cardiologic evaluation including echocardiogram and Holter ECG did not display any pathological feature. Brainstem auditory, visually and sensorial evoked potentials showed augmented latency. Electroencephalograph studies revealed diffuse anomalies with focal sharp waves in parieto–occipital–temporal areas. Magnetic resonance imaging of the brain showed bilateral dilatation of the ventricular system and delayed myelination in semioval centers with cortical and subcortical atrophy and magnetic resonance imaging of spinal cord was normal. High-resolution chromosome, FISH analysis of the subtelomeric regions of all chromosomes, molecular FMR1, PLP1, MCP2, CDKL5 and ARX gene analysis results were normal.

Since the clinical findings as well as the thyroid hormone abnormalities suggested AHDS, the SLC16A2 gene was evaluated for mutations using the SSCP and sequencing methods of the 6 amplified exons of the gene in the proband and both parents and a half-sister that mother had from a previous marriage.

Section snippets

Results

Tests involving thyrotropin-releasing hormone (TRH) carried out using TRH Ferring (Protirelin, Ferring Arzneimittel GmbH, Germany) showed only a minor increase of TSH after i.v. administration of 80 μg (7 μg/kg) of thyrtropin-releasing hormone (Table 2).

DNA analysis of the SLC16A2 gene revealed that the patient was hemizygote for a 4 nucleotide insertion (GCCC) between the 1343 and 1344 nucleotide positions, 1343–1344insGCCC, that creates a frameshift resulting in a downstream STOP codon at

Discussion

We report a patient with Allan–Herndon–Dudley syndrome (AHDS) with severe neurological abnormalities and a SLC16A2 gene mutation. SLC16A2 encodes an active and specific thyroid hormone transporter, MCT8, and mutations in SLC16A2 result in abnormally high levels of serum T3, low or normal T4 levels and TSH in the upper normal range.

Mutation analysis of SLC16A2 gene in this patient revealed the presence of a new frameshift mutation, 1343–1344insGCCC in exon 4. This four nucleotide insertion

Acknowledgements

The authors sincerely thank Prof Antonio Cao and Prof. Samuel Refetoff (University of Chicago, Chicago, IL, USA) for their precious suggestions during manuscript preparation. The authors are also grateful to Prof. Samuel Refetoff and to Prof Roger E Stevenson (Greenwood Genetic Center, Greenwood, SC, USA) for their kind permission to report unpublished data of some AHDS patients. The authors state that there are no conflicts of interest.

References (26)

  • A.M. Dumitrescu et al.

    Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice

    Endocrinology

    (2006)
  • A.M. Dumitrescu et al.

    Novel biological and clinical aspects of thyroid hormone metabolism

    Endocr. Dev.

    (2007)
  • E.C.H. Friesema et al.

    Mechanisms of disease: psychomotor retardation and hugh T3 levels caused by mutations in monocarboxylate transporter 8

    Nat. Clin. Pract. Endocrinol. Metab.

    (2006)
  • Cited by (32)

    • Disorder of thyroid hormone transport into the tissues

      2017, Best Practice and Research: Clinical Endocrinology and Metabolism
    • Inherited defects in thyroid hormone cell-membrane transport and metabolism

      2014, Best Practice and Research: Clinical Endocrinology and Metabolism
      Citation Excerpt :

      Dystonia and involuntary movements commonly occur with the progress of the disease. Characteristic paroxysms of kinesigenic dyskinesias provoked by somatosensory stimuli have been reported in several patients [28,29]. In addition, true seizures occur in 25% of the patients.

    • The syndromes of reduced sensitivity to thyroid hormone

      2013, Biochimica et Biophysica Acta - General Subjects
      Citation Excerpt :

      In addition, true seizures occur in one quarter of the patients. Difficulty falling asleep and frequent awakenings, can represent an important clinical issue for caregivers [82]. Reflexes are usually brisk and clonus is often present.

    • Allan-Herndon-Dudley syndrome (AHDS) in two consecutive generations caused by a missense MCT8 gene mutation. Phenotypic variability with the presence of normal serum T3 levels

      2013, European Journal of Medical Genetics
      Citation Excerpt :

      After obtaining informed consent, genomic DNA of the proband, the maternal uncle and other family members (IV-2, IV-3, III-1, III-2, III-3, III-4, II-2, II-4, II-6, II-7, I-2, in Fig. 1) was extracted from peripheral lymphocytes by standard methods. Mutation detection was performed by direct sequencing of the 6 amplified exons of the MCT8 gene using appropriate pairs of primers (primer sequences available upon request) as previously described [6]. Since the clinical findings as well as the TH abnormalities suggested AHDS, the MCT8 gene was tested for mutations.

    View all citing articles on Scopus
    View full text