This article originally appeared in San Antonio Medicine, the official publication of the Bexar County Medical Society, September 2026, Vol. 79, No. 9.
By William F. Trigoso, MD and Tina Copple, DNP
Ever since we were in medical school, to get to know about rare disorders was basically a rhetorical exercise in futility. We learned them superficially to pass exams, memorized a unique pathophysiology, and hoped we would never encounter these patients. We had virtually nothing to offer outside of a referral to a distant research facility, hoping they might qualify for an obscure study, never to return to our care.
Targeted therapies have fundamentally changed this paradigm, sharpening our clinical awareness and enabling us to recognize these rare conditions in daily practice. These treatments do more than optimize an individual’s immediate quality of life. The presence of an affected patient in our clinic opens a vital door for their descendants. By leveraging cascade screening and early genetic testing, we can intervene in second and third generations at an asymptomatic stage. This shifts our role from reactive management to true prevention, halting systemic deterioration before it begins for the next generation. Nowadays there are many disorders where new therapeutic and preventive measures are within the scope of most physicians. Two pearls to begin looking are X-linked Hypophosphatemia (XLH) and Familial Chylomicronemia Syndrome (FCS).
Pediatric medicine frequently encounters rare, monogenic disorders that disrupt vital pathways. While XLH and FCS represent completely different biochemical pathologies, one affecting skeletal mineralization and the other disrupting lipid metabolism, both present unique diagnostic challenges during early childhood. They require systematic clinical screening and specialized lifelong management to prevent catastrophic complications like permanent bone deformities or disabling recurring pancreatitis.
X-Linked Hypophosphatemia (XLH) in Children
XLH is an inherited skeletal disorder characterized by profound renal phosphate wasting and is the most common heritable rickets. This rare disease affects male and female patients and is caused by the dominant loss-of-function mutation in the PHEX gene.
Under healthy conditions, the PHEX protein counterbalances Fibroblast growth Factor 23 (FGF23), an osteocyte-secreted hormone regulating systemic phosphate balance. When PHEX is mutated, circulating FGF23 rises to pathologically high levels, preventing kidneys from reabsorbing phosphate while suppressing active Vitamin D (1,25(OH)2D) production, resulting in chronic hypophosphatemia and failed bone mineralization.
The clinical presentation can begin in the first two years of life as weight-bearing begins. The phenotype can be mild with no clinical manifestations to severe manifestations resulting in disability. Progressive bowing of lower extremities leads to lower extremities genu varum or genu valgum, distinct waddling gait, short stature. Other manifestations include spontaneous dental abscesses often without any caries notes, that occurs more often than in the average pediatric population. Severe cases may suffer from craniosynostosis.
Diagnosis requires pairing the clinical suspicion presentation with everyday biochemical labs and later molecular profiles. The hallmark of XLH is low fasting serum phosphorus with renal phosphate wasting. The patient will have a normal calcium and normal Vitamin D hydroxy. Confirmation can be confirmed by obtaining a FGF23 level and/or PHEX gene testing through commercial laboratories.
Today, therapeutic management strategies are moving beyond previous therapy that relied on oral phosphate and active Vitamin D (calcitriol), which resulted in mixed outcomes. Now, with targeted biologic therapy, treatment burden along with outcomes have improved over previous therapy.
More recently the current pediatric standard of care is burosumab, a recombinant human IgG1 monoclonal antibody directed against FGF23 that can be administered in the office setting. Burosumab optimizes and neutralizes excess circulating FGF23, restoring normal renal tubular phosphate reabsorption, elevating serum phosphorus, increasing active Vitamin D production, and healing rickets.
Patient that are not identified earlier may also need corrective osteotomies and physical therapy. Regular dental care to monitor caries and abscess is also necessary.
Not only can this improve the patient’s outcomes and quality of life, but also counsels parents/families on the importance of gene testing as males with the gene PHEX variant pass to all daughters but no sons. If a female is positive for the variant PHEX gene, all of her children have a 50% chance of inheritance. The PHEX gene variant has 100% penetrance. It is pivotal to identify children, if possible, by age 6 months as there is therapy that can return phosphate to normal range and limit allowing the body to mature with normal phosphate homeostasis.
Familial Chylomicronemia Syndrome (FCS)
FCS is an autosomal recessive metabolic disorder disrupting dietary fat clearance from the bloodstream. Once dietary fats are packaged into large, triglyceride-rich chylomicrons, they may remain in circulation for a long time unless Lipoprotein Lipase (LPL), an enzyme that sits on the vascular endothelium, breaks down these chylomicrons into free fatty acids, and removes them from the circulation.
Any significant loss of LPL function prevents chylomicron clearance leading to a toxic buildup of circulating triglycerides regularly exceeding 1,000mg/dl to 10,000mg/dl.
The classic academic presentation in infants and children we were familiarized with was a phlebotomy tube with milky plasma. Such a finding would make Dr. House run to the lab in panic. But before we go that route, we can review other symptoms, which include failure to thrive and babies with chronic refractory colic. Also, unexplained frequent pancreatitis that might lead to potential organ failure, that in severe cases could be fatal. Eruptive Xanthomas and lipemia retinalis when seen are diagnostic but are hard to catch in clinical practice, but more often than not are tools of torment by board examiners. The more frequently seen are systemic indicators like failure to thrive, hepatosplenomegaly and severe refractory colic.
FCS in its purer form is rare, but on the other hand it is not infrequent for us to see patients with symptomatology and very high triglycerides (between 750 and 1000) — those are labeled as multifactorial chylomicronemia syndrome (MCS) triggered by secondary factors like diabetes hypothyroidism medications and obesity, which once resolved the problem. The FCS ones will not respond to the conventional treatments (fibrates and omega-3 fatty acids). In addition to clinical presentation, occasional genetic testing could be required for diagnosis.
Traditional lipid-lowering drugs fail in FCS because they rely on an operational LPL enzyme system. Ultra-Low-Fat Nutrition is the primary management approach, restricting dietary fat intake to less than 10% to 15% of daily calories (roughly 10 to 15 grams of fat per day). Medium-Chain Triglyceride (MCT) Oil is utilized as pure MCTs bypass chylomicron formation entirely. They enter the portal vein directly to travel to the liver, providing essential caloric intake without elevating serum chylomicrons. Novel RNA-targeted therapeutics such as APOC3 inhibitors are approved for adults — currently there are clinical studies seeking FDA approval for age 2-18. Once approved, the focus of treatment will be to alleviate this severe disability disorder in children.
If a patient checks positive for either standard lab or clinical parameters above, initiate immediate confirmatory molecular testing (PHEX gene for XLH; LPL/APOC2/GPIHBP1 panel for FCS). Once confirmed, leverage cascade screening to test siblings and parents at an asymptomatic stage, halting systemic deterioration before it begins for the next generation.
The evolving clinical landscapes of XLH and FCS highlight a paradigm shift in pediatric medicine. Rare genetic conditions are no longer theoretical footnotes relegated to academic examinations, but lab tests that can be ordered at the appointment.
As this is an overview, please review clinical guidelines and recommendations.
References:
- Haffner D, et al. (2019). Clinical practice recommendations for the diagnosis and management of X-linked hypophosphatemia. Nature Reviews Nephrology, 15(7), 435–455.
- Imel EA, et al. (2019). Burosumab versus conventional therapy in children with X-linked hypophosphatemia. The Lancet, 393(10186), 2416–2427.
- National Lipid Association. (2025). Expert clinical review on familial chylomicronemia syndrome (FCS). Journal of Clinical Lipidology, 19(2), 110–125.
- Moulin P, et al. (2018). Guidelines for the diagnosis and management of familial chylomicronemia syndrome. Atherosclerosis, 275, 183–194.
- Gario, B., & Moulin, P. (2024). Efficacy and safety of next-generation APOC3 inhibitors in severe hypertriglyceridemia. The Lancet Diabetes & Endocrinology, 12(4), 245–256.
- A Study of Olezarsen for the Treatment of Familial Chylomicronemia Syndrome (FCS) in Pediatric Participants, a study on Chylomicronemia Syndrome.