[A family with Allan-Herndon-Dudley syndrome due to SLC16A2 gene mutation]

Objective: To report a family diagnosed with Allan-Herndon-Dudley syndrome (AHDS) due to SLC16A2 gene mutation and to summarize the phenotypes, genotypes, diagnosis, treatment, and prognosis. Methods: The clinical features of a family of AHDS diagnosed in Xiangya Hospital of Central South University in November 2017 were analyzed. Related literature was searched at Online Mendelian Inheritance in Man (OMIM), PubMed, CNKI and Wanfang database (from the establishment of databases to June 2018) by using "Allan-Herndon-Dudley syndrome" , and "AHDS" as keywords and the case reports from April 2013 to June 2018 were reviewed. Results: The proband was a boy aged 8 months who presented with global developmental retardation, inability to hold up the head, disability to sit independently or grab, no language development, elongated face, big ears, esotropia, scoliosis, hypotonia in the trunk, hypertonia in extremities, and hyperreflexia. Brain magnetic resonance imaging (MRI) showed widening of the extracerebral space and delayed myelination. Thyroid function tests revealed increased FT3, decreased FT4 and normal TSH. Whole exome sequencing (WES) revealed the SLC16A2 gene c.431-1 (IVS1) G>C hemizygous mutation. The infant's mother and grandmother are carriers, but whose father had no related mutation. One uncle from maternal side had severe psychomotor retardation as well as dystonia and died at one year of age with unknown etiology. A total of 97 articles were retrieved in which 19 case reports were reviewed. Forty-two cases (22 from 8 families and 20 sporadic) were reported. Among these 42 cases (all males), all of them presented with moderate to severe cognitive dysfunction, 15 with seizures; 36 were bedridden, only 4 could walk; 31 had no language development, 2 could speak sentences, 4 could speak few words, 1 had babbling sounds. Furthermore,16 had microcephaly, 18 had facial dysmorphism, 6 had esotropia, 2 had hearing loss,14 had scoliosis, 11 had joint contracture, 30 had low body weight/muscle wasting, 37 had hypotonia in trunk or extremities, 32 had progressive spastic paraplegia or hypertonia. In terms of thyroid function, 33 had abnormal results, within whom 30 had increased T3, 25 had decreased T4 and 3 had increased TSH. Brain MRI showed delayed myelination in 22 cases, within which one normalized with development. Genetic tests showed that 31 had missense mutation (14 sporadic), 5 had deletion mutation (3 sporadic, and 1 due to frameshift mutation), 5 had insertion mutation (2 sporadic), and 1 had repeated mutation. The prognosis was poor as patients often died of recurrent respiratory tract infection. Conclusions: The main clinical manifestations of AHDS are severe global developmental retardation, hypotonia, spastic paraplegia, abnormal serum levels of thyroid hormone and delayed brain myelination. SLC16A2 c. 431-1 (IVS1) G > C mutation is accountable for this disease.