Iodine plays a critical role in producing thyroid hormones essential for brain development. An imbalance of iodine, whether deficiency or excess, can disrupt thyroid function. Iodine-induced hypothyroidism is rare but has been reported, particularly in premature infants exposed to excess iodine. Currently, iohexol, a nonionic radiocontrast agent, has limited data but is considered compatible with breastfeeding. A small for gestation African American male neonate was born at 36 weeks and 3 days of gestation and admitted to the neonatal intensive care unit for respiratory distress and prematurity in the United States. Samples for Illinois newborn screens done at admission and repeated after 48 h of life were negative for thyroid abnormalities. On the infant's fifth day of life, the mother underwent a contrast-enhanced imaging study using iohexol, after which the infant received breast milk from days 5-11. On day 11, the neonate had an elevated thyroid-stimulating hormone (TSH) and low free thyroxine (T4) levels, consistent with hypothyroidism. Urine iodine level in the infant was checked and found to be elevated, prompting concern for the exposure to iodine in breastmilk. However, the need to increase the levothyroxine dose to achieve normal thyroid levels was not consistent with a transient effect such as iodine exposure. Genetic testing revealed a likely pathogenic intragenic deletion in the gene RPS6KA3, consistent with Coffin-Lowry syndrome, as well as two variants of unknown significance (VUS) in IYD. This case highlights the complex interplay between genetic factors and environmental influences in the development of neonatal hypothyroidism. While iodine contrast exposure through breast milk is generally considered safe, this case underscores the potential risks in preterm infants. Initially, iodine exposure through breastmilk was considered a likely contributor to thyroid dysfunction, but with further time and evaluation, congenital thyroid dysgenesis with underlying genetic findings complicated the diagnosis. This case demonstrates the importance of a comprehensive evaluation when working up thyroid dysfunction to exclude other potential etiologies before interrupting breastfeeding.

Galactosemia is a congenital disorder of carbohydrate metabolism, in which the body is unable to metabolize galactose properly. Coffin-Lowry syndrome (CLS) is characterized by intellectual disability, developmental delay, dysmorphic features, growth retardation, vision and hearing loss, and skeletal changes, which is an X-linked disorder, with males being more severely affected, whereas the clinical findings in females show variability. This case is presented due to the rare concomitance of galactosemia and CLS. A 2-year-old female patient, previously diagnosed with galactosemia, who had good dietary adherence was noticed to have developmental delay, dysmorphic features, nephrolithiasis and recurrent pericardial effusions during follow-up. Further research was carried out to diagnose an underlying second disease. Metabolic tests were inconclusive. Clinical exome sequencing (CES) analysis, revealed a heterozygous c.472C>T p. (Arg158Cys) pathogenic variant in RPS6KA3 (OMIM #300075) and CLS (OMIM #303600) was diagnosed. This case report is a unique summary of a patient with galactosemia who further was diagnosed with CLS that emphasizes the possibility of co-occurrence of rare diseases and highlights the importance of conducting further investigations in patients with unexplained findings in the context of existing metabolic diseases.

To investigate the clinical phenotypes and genotypic characteristics of Chinese patients with Coffin-Lowry syndrome. The clinical data and genetic test results of a family with Coffin-Lowry syndrome were retrospectively analyzed. A literature review was conducted to summarize the clinical characteristics and gene mutation characteristics of patients with Coffin-Lowry syndrome in China. The proband was a 1-year-old boy with distinctive facial features, puffy but tapered fingers, hypotonia, growth retardation, and delayed cognitive and motor development. Genetic analysis revealed a hemizygous c.1603-2A>G mutation in intron 17 of the RPS6KA3 gene in the proband. His mother was a heterozygous carrier. The identified mutation has not been reported previously. The proband's maternal half-brother and half-sister also exhibited similar clinical manifestations and were diagnosed with Coffin-Lowry syndrome together with the proband. The proband was followed up until 3 years and 8 months old, by which time he was not capable of walking steadily independently or speech. Including the 4 members of this family, a total of 28 Chinese patients were identified. Their clinical manifestations included special facial features (100%), cognitive and language/motor developmental delays (92.6%), hypotonia (95.2%), tapered fingers (88.5%), and scoliosis or kyphosis (45%). Genetic sequencing was performed in 24 patients, revealing missense mutations in 3 cases (12.5%), frameshift mutations in 5 cases (20.8%), nonsense mutations in 9 cases (37.5%), splice-site mutations in 4 cases (16.7%), and exon deletions in 2 cases (8.3%). No mutation hotspots were identified. Coffin-Lowry syndrome should be considered in children with cognitive and language/motor developmental delays, distinctive facial features, tapered fingers, and hypotonia. Genetic testing can assist with early diagnosis. 探讨中国Coffin-Lowry 综合征患者的临床表型及基因型特征。 回顾一个Coffin-Lowry 综合征家系的临床资料及基因检测结果，并复习文献，总结中国Coffin-Lowry 综合征患者的临床特点及基因突变特点。 患儿，男，1岁，有特殊面容、锥形手指、肌张力低下、生长迟缓，认知运动发育落后。患儿RPS6KA3基因17号内含子上发生c.1603-2A>G半合子突变，母亲发生杂合突变，该变异是首次报告。其同母异父的哥哥和姐姐也有相似的临床表现，与患儿一并诊断为Coffin-Lowry综合征。该患儿随访到3岁8月，独走不稳，无语言出现。包括该家系4人，共有28例中国患者，表现为特殊面容（100%），认知及语言运动发育迟滞（92.6%）、肌张力低（95.2%）、锥形手指（88.5%）、脊柱侧弯/后凸(45%)等。共有24个患者行基因测序，其中错义突变3例( 12.5%)，移码突变5例（20.8%），无义突变9例（37.5%），剪接突变4例（16.7%），外显子缺失2例（8.3%），未出现变异热点。 患儿有认知及语言运动发育迟缓，特殊面容伴有锥形手指、肌张力低下时应考虑Coffin-Lowry 综合征；基因检测有助于早期诊断。

The ribosomal protein S6 kinase family members play essential biological functions in disease, from cancer to intellectual disability. Little is known about ribosomal proteins S6 kinase C1 (RPS6KC1), aside from its lack of phosphorylation capacity and its roles in sphingosine-1-phosphate signaling and peroxiredoxin-3 (PRDX3) transport to mitochondria. Through whole-exome sequencing, we identified bi-allelic RPS6KC1 variants in 13 individuals from 8 independent families. Phenotypic manifestations included neurodevelopmental delay, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome caused by RPS6KA3 mutations. Functional studies on peripheral blood mononuclear cells (PBMCs) from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and sphingosine kinase 1 (SPHK1), accompanied by marked repression of the mammalian target of rapamycin (mTOR)/phosphatidylinositol 3-kinase (PI3K) pathway. We detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Further studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan. These findings underscore the crucial roles of RPS6KC1 in neurodevelopment by controlling ribosomal protein synthesis, lipid signaling, and the mTOR pathway.

We present the case of a 15-year-old girl with new-onset psychosis and abnormal white matter activity on neuroimaging, engaging multidisciplinary care between genetics, neurology, psychiatry, and neuropsychology. She functioned well in mainstream education despite below average intellectual functioning. Physical examination findings enabled the diagnosis, and patient improved with joint psychological and behavioral outpatient services.