Rathbun syndrome (hypophosphatasia) due to the heterozygous variant c.297+5G>A in alkaline phosphatase with unusual phenotype

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Rathbun syndrome (hypophosphatasia) due to the heterozygous variant c.297+5G>A in alkaline phosphatase with unusual phenotype

Rare metabolic disorders often reveal surprising ways the body’s systems connect—especially when symptoms appear in organs no one expects. Hypophosphatasia (HPP), a genetic condition that impairs bone health, is typically linked to skeletal issues like weak bones or fractures. But a 2022 case study of an adult woman with HPP, published in the Chinese Medical Journal, has uncovered symptoms never before associated with the disorder, highlighting how little we still know about this condition.

What Is HPP?

HPP is caused by variants in the ALPL gene, which produces tissue-non-specific alkaline phosphatase (TNAP)—an enzyme critical for healthy bones, muscles, brain, liver, and kidneys. When TNAP activity drops, bones fail to mineralize properly, leading to fragile bones, osteoid buildup (unmineralized bone tissue), and a higher risk of fractures. While HPP mainly affects the skeleton, it can occasionally impact non-bone organs like muscles or the brain.

Josef Finsterer (Department of Neurology) and Claudia Stöllberger (2nd Medical Department with Cardiology and Intensive Care Medicine), both at Klinik Landstrasse in Vienna, Austria, shared the case of a 49-year-old woman whose HPP presented with unusual multi-system symptoms.

The Patient’s Story

The woman had a complex medical history spanning decades:

  • Childhood: Attention deficit hyperkinesia syndrome (ADHS) and a right ankle fracture.
  • Adulthood: Hashimoto thyroiditis (age 26), bipolar disorder (29), progressive muscle weakness with severe myalgias (muscle pain) and elevated creatine kinase (a marker of muscle damage, peaking at 2500 U/L; normal ranges are ~26–140 U/L) (30), low alkaline phosphatase (34), hyperuricemia (36), hypertension (39), breast cancer (40), hyperostosis frontalis (thickening of the forehead bone, 40), ostealgia (bone pain, 43), moderate mitral insufficiency (47), and heart failure (49).

She also had keratoconus (thinning of the cornea), hyperlipidemia (high cholesterol), and a hiatal hernia. Her family history included breast cancer (mother, maternal grandmother, great-grandmother), pancreatic cancer (great-aunt), diabetes (mother), myocardial infarction (mother), dementia (mother), osteopenia (mother), and polyarthritis (sister)—but no one in her family had HPP.

Diagnosing HPP

When doctors investigated her low alkaline phosphatase (a red flag for HPP) and ostealgia, genetic testing revealed the ALPL variant c.297+5G>A—confirming HPP. But her symptoms were far from typical.

Most HPP patients experience skeletal features like reduced bone mineralization, premature suture closure, bone deformities, dwarfism, early tooth loss, or prolonged bone healing. Extra-osseous features (affecting non-bone tissues) are rare but include seizures, myopathy (muscle disease), or kidney failure.

This patient’s symptoms—ADHS, bipolar disorder, Hashimoto thyroiditis, hypertension, hyperlipidemia, breast cancer, heart failure, keratoconus, and QT-prolongation (abnormal heart rhythm)—had never been reported in HPP before.

Why the Unusual Symptoms?

The authors noted two key explanations:

  1. A second metabolic disorder: TNAP (the enzyme affected by HPP) is not highly expressed in the heart, eyes, endocrine glands (e.g., thyroid), or breasts—where many of her symptoms occurred. Since family members had some of these issues (e.g., breast cancer, diabetes) but not HPP, a separate, undiagnosed condition may have been present.
  2. Medication effects: Her hepatopathy (liver damage) was likely due to long-term valproic acid use—a common bipolar disorder treatment known to affect the liver.

Key Takeaways

This case challenges what we know about HPP. While the ALPL variant confirmed the diagnosis, the patient’s unique symptoms remind us that rare diseases can manifest in unexpected ways. For clinicians, the message is clear: low serum alkaline phosphatase + ostealgia = consider HPP—even if other symptoms seem unrelated. For patients, it’s a reminder that complex health histories require thorough, interdisciplinary testing.

The patient did not receive asfotase alfa (the enzyme replacement therapy for HPP) or a bone marrow transplant. She was discharged on medications for heart failure (enalapril, hydrochlorothiazide, furosemide), high cholesterol (atorvastatin), bipolar disorder (valproic acid), and anxiety (midazolam).

References

  1. Stürznickel J, Schmidt FN, von Vopelius E, et al. Bone healing and reactivation of remodeling under asfotase alfa therapy in adult patients with pediatric-onset hypophosphatasia. Bone. 2021;143:115794.
  2. Fonta C, Salles JP. Neuromuscular features of hypophosphatasia. Arch Pediatr. 2017;24:5S85–5S88.
  3. Sharma N, Bache E, Clare T. Bilateral femoral neck fractures in a young patient suffering from hypophosphatasia, due to a first time epileptic seizure. J Orthop Case Rep. 2015;5:66–68.
  4. Krohn-Grimberghe B, Ludwig B, Furkert D. Rathbun-Syndrom (Hypophosphatasie). Klinisch: Minderwuchs und Bechterew-Symptomatik [Rathbun syndrome (hypophosphatasia). Clinical aspects: dwarfism and Bechterew symptoms]. Z Rheumatol. 1991;50:387–391.
  5. Collmann H, Mornet E, Gattenlöhner S, et al. Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst. 2009;25:217–223.
  6. Whyte MP, Leelawattana R, Reinus WR, et al. Acute severe hypercalcemia after traumatic fractures and immobilization in hypophosphatasia complicated by chronic renal failure. J Clin Endocrinol Metab. 2013;98:4606–4612.

doi:10.1097/CM9.0000000000001777

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