BMC Pediatrics · 3 authors, 3 centres
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This case report describes a 3-month-old boy with Coffin-Lowry syndrome (CLS) who presented with very severe hypertriglyceridemia (32 mmol/L or 2834 mg/dL) of unknown cause. The hypertriglyceridemia was transient and resolved with dietary modification using medium-chain triglyceride formula. This suggests that very severe hypertriglyceridemia may be an unrecognized clinical feature of CLS, expanding its phenotype.
**Background:** Coffin-Lowry syndrome (CLS) is a rare X-linked semi-dominant disorder characterized by psychomotor and growth retardation, facial dysmorphism, digit abnormalities, and progressive skeletal changes, caused by mutations in the RPS6KA3 gene. While CLS has multisystemic manifestations, hypertriglyceridemia (HTG) has not been previously reported in association with CLS. HTG is defined as triglyceride (TG) concentrations >150 mg/dL and is extremely uncommon in infancy. This case report presents a male infant with very severe HTG detected incidentally at 3 months of age, who was later diagnosed with CLS.
**Methods:** This is a case report of a single patient. The patient was a male infant born at 35 weeks via elective cesarean section due to intrauterine growth restriction (IUGR), with a birth weight of 2.1 kg. He had neonatal jaundice treated with phototherapy. At 3 months of age, routine blood sampling revealed lipemic plasma, and a repeat sample after 4 hours of fasting showed very severe HTG: TG 32 mmol/L (2834 mg/dL), total cholesterol 8.1 mmol/L, HDL 0.45 mmol/L, AST 87 U/L, GGT 374 U/L. Hepatic steatosis was seen on ultrasound. Breast milk was substituted with Portagen formula (medium-chain triglyceride formula). Over time, the patient developed global developmental delay and dysmorphic features consistent with CLS (hypertelorism, downslanting palpebral fissures, frontal bossing, flat nasal bridge, maxillary hypoplasia, thick lower lip, pectus carinatum, tapering fingers, fleshy palms). Brain MRI showed generalized reduced white matter volume with mild ventriculomegaly. Whole exome sequencing revealed a hemizygous mutation in RPS6KA3 (c.748G>A, p.Asp250Asn), confirming CLS. No pathogenic mutations for HTG were found. Secondary causes of HTG (diabetes, obesity, hypothyroidism, renal disease, medications) were ruled out.
**Key Results:** The patient's TG levels improved dramatically with Portagen formula: at 4 months, TG was 2.55 mmol/L; at 6 months, 2.4 mmol/L; at 8 months, 2.66 mmol/L; at 1 year 8 months, 1.8 mmol/L; at 2 years 8 months, 2.52 mmol/L; and at 3 years 4 months, 1.22 mmol/L. He was able to return to a normal diet at approximately 2 years old with decent TG levels. The RPS6KA3 variant was classified as a variant of uncertain significance, likely due to the rarity of CLS and lack of genomic data in the Asian population. The variant is suspected to be de novo, as the mother has normal intellect and no features of CLS.
**Clinical Implications:** This case suggests that very severe HTG may be an unrecognized clinical feature of CLS, expanding its phenotype. The HTG was transient and resolved with age and dietary modification. Early detection of very severe HTG is important because it can lead to pancreatitis (risk 10-20% with TG >2000 mg/dL) and premature cardiovascular disease. As genetic testing becomes more common, more infants with CLS may be diagnosed earlier, allowing for better phenotyping and management. The mechanism of HTG in this case is unclear, but it may be related to CLS itself, possibly through the RPS6KA3 gene's role in cellular signaling pathways affecting lipid metabolism. The case also highlights the importance of considering CLS in infants with unexplained very severe HTG and dysmorphic features.