コフィン・ローリー症候群

BACKGROUND: Coffin-Lowry syndrome (CLS, OMIM #303600) is an X-linked dominant inherited condition caused by variants in the RPS6KA3 gene located at Xp22.12 and mainly affects men. It is associated with various phenotypes, including dysmorphic facial features, neurodevelopmental impairment, short stature, and skeletal deformities. The objective was to present a case of CLS, describe the clinical manifestations found, compare it with what is reported in the literature and collaborate in expanding the phenotypic and molecular spectrum, because it presents a previously unreported variant. CLINICAL CASE: A 4-year-old male, son of healthy, non-consanguineous parents, who presents distinctive clinical features of CLS: global neurodevelopmental delay, hypertelorism, low-set and prominent ears, down-slanted palpebral fissures, depressed nasal bridge, anteverted nostrils, wide mouth, widely spaced teeth, and broad fingers. Genetic analysis revealed a likely pathogenic hemizygous variant RPS6KA3 c.1762G>A (p. Glu588Lys) associated with CLS. CONCLUSIONS: CLS is a rare entity that is usually diagnosed in childhood. Typical facial changes and specific clinical and radiological signs in the hands are very useful in diagnosis.

Background/Objectives: Coffin-Lowry syndrome (CLS) is a rare X-linked disease caused by pathogenic variants in the RPS6KA3 gene. It is generally characterized by syndromic intellectual disability and distinctive facial features, skeletal abnormalities, stimulus-induced drop attacks in males, and variable manifestations in females. Methods: We report clinical and genetic findings in a series of 10 cases, eight males and two females, evaluated at the Regional Centre of Medical Genetics Dolj-Emergency Clinical County Hospital Craiova. Results: Genetic testing identified 10 de novo variants in the RPS6KA3 gene consisting of six missense mutations, one nonsense variant, one frameshift, and two variants in non-coding or intronic regions. Case management requires multidisciplinary coordination and is limited to resources mostly available in reference centers. Conclusions: CLS highlights the importance of molecular diagnosis in rare genetic disorders, particularly when clinical features are subtle or atypical. These findings have practical implications for clinical management, suggesting the need for comprehensive genetic screening and individualized care approaches.

BACKGROUND: 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. CASE PRESENTATION: 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. CONCLUSIONS: 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.

BACKGROUND: Coffin-Lowry syndrome (CLS) is a rare X-linked disorder caused by pathogenic variants in RPS6KA3, presenting with intellectual disability, distinctive facial and skeletal features, and variable systemic involvement. Advances in genomic technologies have expanded the mutation spectrum, yet genotype phenotype correlations remain incompletely understood. METHODS: We conducted a systematic review of published cases (n = 72) following PRISMA guidelines. Demographic, phenotypic, and genotypic data were extracted, standardized, and summarized using descriptive statistics. Associations between mutation type and key clinical features were assessed with Chi-square or Fisher's exact tests. Diagnostic approaches and global distribution were also analyzed. RESULTS: The cohort comprised 50 males (69.4%) and 22 females (30.6%), median age 12 years (range: 1-45). Developmental delay (87.5%) and intellectual disability (66.7%) were the most frequent features, alongside musculoskeletal deformities (kyphoscoliosis 33.3%, pectus anomalies 19.4%) and neurologic involvement (SIDEs 12.5%, seizures 15.3%, spasticity 5.6%). Frameshift variants showed the strongest associations with SIDEs (35%, p = 0.009) and seizures (24%, p = 0.048), while splice-site mutations were linked to spasticity and cardiomyopathy. No consistent clustering of intellectual disability severity by mutation type was observed. Diagnostic methods varied, with most cases confirmed by sequencing approaches (e.g., Sanger, WES, next-generation sequencing panels), supplemented by array-based CNV detection. Geographically, cases were reported across Asia, Europe, and North America, with the largest clusters from China (14), USA (14), and Japan (9). CONCLUSION: This systematic review highlights recurrent neurodevelopmental, neurologic, and skeletal phenotypes in CLS and delineates mutation-specific risks, particularly for SIDEs and seizures. The findings emphasize the value of comprehensive genomic testing, raise awareness of maternal germline mosaicism, and underscore the utility of reproductive technologies such as PGT-A/M for at-risk families. Beyond clinical and research implications, this work provides an accessible reference for affected families seeking clearer prognostic insights. SYSTEMATIC REVIEW REGISTRATION: Identifier CRD420223404871.

OBJECTIVE: To investigate the clinical phenotypes and genotypic characteristics of Chinese patients with Coffin-Lowry syndrome. METHODS: 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. RESULTS: 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. CONCLUSION: 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.