A Novel Mutation Diagnosing in Allan–Herndon–Dudley's Syndrome

Abstract

Allan–Herndon–Dudley's syndrome (AHDS) is a rare X-linked recessive disease that causes abnormal serum thyroid function tests, severe hypotonia, intellectual disability, and motor deficit due to a mutation in the monocarboxylate transporter 8, which is a thyroid hormone transporter. A 6-month-old male patient presented to our outpatient clinic with a serious hypotonia complaint. With a preliminary diagnosis of AHDS, a molecular genetic examination was performed. The molecular genetic analysis detected a new previously unidentified variant in the SLC16A2 gene. This case has been presented to report the AHDS, which is a rare cause of hypotonia in patients presenting/consulting with severe hypotonia, global developmental delay, and abnormal thyroid function test results. Besides, a novel pathogenic mutation in the SLC16A2 gene has been described in the present article.

Introduction

Allan–Herndon–Dudley's syndrome (AHDS) is an X-linked recessive syndrome, characterized by congenital hypotonia, intellectual disability, spastic paraparesis, and abnormal thyroid function tests, accompanied by dystonic/athetoic movements. It was first described by Allan et al ¹ in 1944 when hypotonia, developmental delay, and thyroid dysfunction were observed in 24 male patients through six generations of a same family. In 2003, Friesema et al ² first found the association of this disease with the gene encoding the monocarboxylate transporter 8 (MCT8) of the thyroid hormone.

Background

MCT8 is an active thyroid hormone transporter, intrinsic to neurons. ³ Mutations in the SLC16A2 gene, encoding MCT8, a specific transporter for the thyroid hormone, result in AHDS. Thus, severe psychomotor retardation, hypotonia, and peripheral thyrotoxicosis are developed as a result of the mutation in the SLC16A2 gene. While widespread hypotonia, poor head control, and speech delay are detected in these patients from the first year of life, spastic quadriplegia and muscle atrophy-dependent axial hypotonia are observed in later stages. ^{4 5 6}

Clinical Manifestation

AHDS is a rare X-linked recessively inherited syndrome, accompanied by hypotonia in the infantile period and thyroid hormone abnormalities. This syndrome consists of high fT3, normal/low fT4, and normal/slightly high thyroid-stimulating hormone (TSH). ⁷

Diagnosis

The AHDS was diagnosed as a consequence of a mutation in the SLC16A2 gene, abnormal thyroid function tests, delay in cerebral and cerebellar myelinization in magnetic resonance imaging (MRI), and X-linked inheritance.

Management

Since this is a genetic disease, there is no definite and supportive treatment, whereas physical medicine and treatment as well as special education can be applied.

Prognosis

In the literature, different clinical features ranging from mild intellectual disability to severe encephalopathy have been presented for AHDS. ⁸ In the study by Wang et al, ⁹ five male patients changing from 8 months to 8 years old were defined; in all patients, developmental delay with severe intellectual disability, inability to sit, poor head control, and poor response to external stimuli were reported. Friesema et al ⁷ observed similar findings in five male patients having poor head control, severe intellectual disability, and speech disorder. Besides, in a large case series by Schwartz et al, ⁴ it was emphasized that there are patients with mild phenotypic features, as in our case.

Case Presentation

The present article is aimed to describe a new pathogenic mutation that was previously unidentified in the SLC16A2 gene and to keep in mind the AHDS that is the rare cause of hypotonia.

A 6-month-old male patient ( Fig. 1A , individual number III-11 in the pedigree) was born on time by a 3,600 g normal spontaneous vaginal route and presented to our outpatient clinic with a complaint of poor head control. There was no parental consanguinity; however, there were two male cousins (maternal aunt's children) having similar characteristics ( Fig. 1A , individual numbers III-4 and III-5 in the pedigree). On physical examination, there were a mild myopathic facial appearance (inverted V-shaped upper lip with short philtrum, and tented mouth) (as shown in Fig. 1B ), normoactive deep tendon reflexes, severe hypotonia, and psychomotor developmental retardation. Denver developmental screening test showed a developmental delay in personal social, fine motor, gross motor, and language areas. Head circumference and the height and weight measurements were within normal limits. Hemogram, blood biochemistry, creatine kinase, ammonia, lactate, and tandem mass spectrometry results were normal. Normal TSH level of 3.05 (0.7–5.9) µIU/mL, low fT4 level of 7.96 pmol/L (8–22), and a high fT3 level of 9.59 pmol/L (3.59–6.71) were detected in the patient. There was a delay in cerebral and cerebellar myelinization in MRI of the brain, while abdominal ultrasonography, echocardiogram, electroencephalography, and electroneuromyography test results were normal. In addition, the patient was evaluated with suspicion of neurogenetic disease.

Fig. 1.

(A) Pedigree of the family, indicating the proband (III-11, arrow), his influenced cousins (III-4 and III-5), and (B) proband (III-11) at 6 months of age.

Based on the appointed findings, molecular genetics performed on the thought of AHDS in the differential diagnosis. All gene sequence analysis was performed for SLC16A2 by using a peripheral blood sample. DNA was isolated with QIAsymphony DSP DNA Midi Kit (Qiaqen, Hilden, Germany); next-generation sequencing was performed via Illumina Miseq (Illumina, California, United States) platform; bioinformatics analyses were made using QCI-A and QCI-I (Qiagen, Hildenberg, Germany). As a result, the mutation of c.1262G > C (p.Gly421Ala) was found as hemizygous variant in the SLC16A2 gene. At the family screening, the mother was found to be heterozygous (carrier) for the same mutation ( Fig. 2 ). The other son of the family is healthy and does not carry the mutation. Although this mutation was not previously reported, it was evaluated as likely pathogenic according to in silico analysis programs. ⁶

Fig. 2.

Mutation images: (A) hemizygote variant in the SLC16A2 gene belonging to the patient and (B) maternal heterozygosity c.1262G > C (p.Gly421Ala).

Discussion

In this case, based on the clinical findings and the presence of two cousins with similar characteristics, a molecular test was performed with a prediagnosis of AHDS. A new pathogenic mutation was detected in SLC16A2 , and hence, AHDS was diagnosed. This case with a new mutation was presented to provide a contribution to the literature.

When our case was examined in terms of hypotonic infant etiology, developmental delay and mild myopathic facial appearance (short filtered inverted V-shaped upper lip and tent mouth) were presented in addition to distinct axial hypotonicity. The absence of spasticity in our patient might be due to the age of our patient, early diagnosis, and appropriate physical therapy. It is known that patients with AHDS were friendly and docile, not prone to aggressive or destructive behavior. ¹⁰ Consistent with the literature, it was observed that our patient generally smiled at his parents and those around him. In addition to a novel mutation, there are recovery in the developmental milestones (such as having full control of head, getting in sitting position without help, crawling, starting to spell, absence of spasticity, knowing the parent) apart from regression in the clinical findings of the outpatient.

The thyroid hormone is critical in order for a normal brain development. Since the thyroid hormone metabolism takes place inside the cell, transporter proteins are needed that facilitate transport in the cell membrane. ¹¹ A mutation in the SLC16A2 gene, encoding MCT8, conduces to absence of T3 and T4 entry in the brain, which results in central thyroid hormone deficiency and an increase in serum fT3 level is observed. ^{4 7 9 12} The biological activity of the thyroid hormone is related to the T3 level inside the cell. In the study by Wang et al, ⁹ normal TSH, low fT4, and high fT3 levels were observed in all patients, while high fT3 level was found in all patients in the study conducted by Friesema et al. ⁷ Also, a high fT3 level was found in patients with mild phenotypic characteristics, included in the large series of Schwartz et al. ⁴ In our patient's thyroid function tests, TSH was normal, and low fT4 and high fT3 levels were found. The presence of this disease may be overlooked depending on the absence of clinical signs of a high fT3 level. Therefore, we would like to emphasize the importance of measuring serum fT3 in patients with developmental retardation who present with hypotonia.

The variant detected in the case was not previously reported, so defined as a new mutation. Although the variant has not been defined before, it was evaluated as a high probability cause of the disease according to Polyphen2, MutationTaster, and SIFT data in “in silico” analyses, and it was classified as a likely pathogenic variant when all data are considered. ⁶

It is aimed to contribute to the literature by emphasizing the AHDS syndrome, which is identified as a new pathogenic mutation in SLC16A2, and that thyroid function tests, especially fT3, should not be forgotten in patients who were examined with hypotonic infant etiology.

Conclusion

There are many diseases in the hypotonic infant etiology. The genetic tests for reaching neurological diagnosis are broadly used in the last stage. However, presenting the novel mutations accompanied with the clinical and laboratory findings to the literature will expand the awareness. As in our patient, maybe early diagnosis will exert a positive influence on the patient prognosis. Presenting such novel mutations to the literature will conduce to early recognization of such current cases.