Rare PHEX variant with insidious presentation leads to a delayed diagnosis of X-linked hypophosphatemia

Abstract

A 7-year-old girl without a significant previous medical history was diagnosed with X-linked hypophosphatemic rickets (XLHR) due to a rare, most likely pathogenic, PHEX gene variant after a 4-year delayed diagnosis due to mild clinical presentation. At 2 years of age, her intoeing and femoral bowing were attributed to physiologic bowing and borderline vitamin D sufficiency, despite phosphorus not being measured. Hypophosphatemia was eventually detected after incomplete improvement of bowing and leg length discrepancy with suboptimal linear growth. This rare PHEX variant (c.1949T>C, p.Leu650Pro) further supported the clinical diagnosis of XLHR. Treatment with burosumab (an anti-FGF23 monoclonal antibody) normalised phosphorus and alkaline phosphatase levels and improved her bowing. The diverse phenotypic presentation of this variant can result in delayed diagnosis and highlights the importance of prompt assessment of phosphorus levels in patients with skeletal deformities to ensure timely recognition and treatment.

Background

Bowing of lower extremities and intoeing may be physiological findings in toddlers; however, they can also indicate metabolic bone disease that is most frequently occurred due to rickets in this age group. The most common type of rickets, nutritional calcipenic rickets, is increasingly prevalent in the USA and worldwide.¹ X-linked hypophosphatemic rickets (XLHR), which accounts for 80% of cases of phosphopenic rickets, is rare (4.8 cases per 100 000) and may not be suspected initially.^{2 3} Additionally, the diversity of XLHR’s phenotypic presentation, the clinical similarities to benign or more common causes and the lack of universal serum phosphorus screening at the initial evaluation of skeletal deformities and poor growth contribute to diagnostic delays and heighten the risk of associated, potentially severe lifelong morbidity.

Case presentation

A 6-year and 9-month-old African American girl was referred to paediatric endocrinology by her orthopaedic specialist for evaluation of hypophosphatemia with mild femoral bowing (left greater than right), mild metaphyseal dysplasia and borderline vitamin D sufficiency.

She was born at term and small for gestational age and was breastfed until 6 months of age. She consumed average amounts of cow’s milk for age and took a daily multivitamin starting at age 2 years. Orthopaedics managed her care since the age of 2 years for physiologic bilateral intoeing and mild metabolic bone disease with mild genu varum attributed to borderline vitamin D sufficiency.

She lacked muscle weakness, fatigue or pain with ambulation, waddling gait, delayed gross motor development, hearing or vision deficits, headaches or dental disease. Her diet was average, and her medical history was negative for fractures and any chronic illnesses. She was growing at the third percentile for height, which was at the low end of her genetic potential. There was no family history of bone disorders or severe short stature (mother’s height 50th percentile, father’s height 25th percentile).

Investigations

At 2-year, 9-month old, lower extremity radiographs (figure 1) showed mild bilateral femoral bowing and mild metaphyseal widening and fraying. Initial laboratory assessments at that time were notable for borderline vitamin D sufficiency (25-hydroxyvitamin D=25 ng/mL; normal 20–100 ng/mL, insufficiency 16–19 ng/mL, deficiency <16 ng/mL, as per definitions set for children by the American Academy of Paediatrics and Institute of Medicine), elevated 1,25-dihydroxyvitamin D (121 pg/mL; normal 31–87), normal intact parathyroid hormone (PTH=43 pg/mL; normal 12–72) and normal serum calcium (9.7 mg/dL; normal 8.5–11). Subsequent orthopaedic assessments until 4 years old revealed unilateral improvement of genu varum (figure 2). At 6 years and 8 months of age, she presented with 1.2 cm leg length discrepancy (right longer than left), persistence of mild metaphyseal dysplasia, and asymmetric bowing with left greater than right (figure 3). At that time, her orthopedist obtained a serum phosphorus level, which revealed hypophosphatemia (1.9 mg/dL; normal 4–5.5), and she was referred to paediatric endocrinology.

Figure 1.

Lower extremity radiograph at 2 years 9 months old.

Figure 2.

Lower extremity radiograph at 4 years old.

Figure 3.

Lower extremity radiograph at 6 years old.

Her initial paediatric endocrinology assessment confirmed hypophosphatemia (2.9 mg/dL) and demonstrated vitamin D insufficiency (16 ng/mL), elevated alkaline phosphatase (ALP 380 IU/L; normal 100–350), normal intact PTH (45 pg/mL), normal serum calcium (10.1 mg/dL), normal serum bicarbonate and normal urinalysis. Since transient hypophosphatemia and elevated ALP can also be seen in vitamin D deficiency rickets, after correction of vitamin D insufficiency (55 ng/mL), phosphorus was repeated and once more confirmed low with elevated ALP. Growth velocity was low to normal, and bone age was concordant with chronological age predicting a final adult height below the first percentile. Her maximal tubular reabsorption of phosphorus per glomerular filtration rate was inappropriately low in the setting of hypophosphatemia (2.18 mg/dL; normal 2.9–6.5), indicating urinary phosphorus wasting. She also had stage 1 hypertension on at least three separate occasions with normal echocardiogram, with concurrent body mass index between the 73rd and 98th percentiles for age and sex.

The presence of rickets and short stature in the setting of persistent hypophosphatemia with urinary phosphate wasting, elevated ALP and normal vitamin D and PTH levels met criteria for the clinical diagnosis of hypophosphatemic rickets.³ Genetic testing by the commercial genetic laboratory Prevention Genetics (Wisconsin, USA) revealed a novel variant in the PHEX gene (c.1949T>C, p.Leu650Pro) (figure 4) that in silico analysis predicted to be pathogenic, using methods previously described by Liu et al and as per American College of Medical Genetics and Genomics guidelines.⁴ This same variant has since been reported in a Korean toddler with bilateral bowing treated with phosphate and calcitriol, further supporting probability of a pathogenic variant.⁵

Figure 4.

PHEX variant Next Generation Sequencing image.

Incidentally, the patient also had a sequence variant in the ALPL gene of unknown significance (c.1381G>A, p.Val461Ile). This variant is more common in patients of African ancestry (2.8%) and has been reported to cause hypophosphatasia and fractures in adults.

Differential diagnosis

The differential diagnosis of bowing includes physiologic bowing and pathologic conditions such as Blount disease, rickets and skeletal dysplasia syndromes. Physiological bowing occurs commonly in toddlers and consists of bilateral symmetric bowing without lateral thrust during ambulation and normal stature; it resolves in early childhood. Femoral metaphyseal dysplasia can be a consequence of vitamin D insufficiency or physiological bowing. Blount disease occurs in older children and has characteristic tibial involvement that our patient was lacking. Skeletal dysplasia syndromes consist of several dysmorphic features including rhizomelic shortening of limbs, frontal bossing, lumbar lordosis, midface hypoplasia and dwarfism that our patient was lacking.

Treatment

The primary treatment goals in XLHR are to maximise growth potential, improve bone health and mitigate associated morbidity. Consistent supplementation with phosphate, calcitriol and vitamin D3, and calcium intake optimisation may improve rickets and bone mineral content. Our patient adhered to dietary calcium supplementation. She initially received daily vitamin D3 4000 IU, which was reduced to 2000 IU orally daily on normalisation of her 25-OH vitamin D levels. Phosphate (250 mg every 6 hours orally) and calcitriol (0.3 μg every 12 hours orally) treatment was not tolerated due to diarrhoea, a common adverse effect, and led to nonadherence. She subsequently started subcutaneous injections of burosumab 0.8 mg/kg/dose every 2 weeks (FDA approved since April 2018 for XLH) with resulting normalisation of her serum and urinary phosphorus and ALP. Her hypertension has been successfully treated to date after her lifestyle modifications improved her body mass index to the 69th percentile.

Outcome and follow-up

Twelve months after initiating burosumab treatment, her serum and urinary phosphorus levels remain normal on burosumab 0.8 mg/kg/dose every 2 weeks. Her ALP also remains normal (380–485 before treatment, normal for age 100–350 IU/L; 258–315 after treatment, normal for current age 100–450 IU/L). Her growth velocity remains at 4.5–4.9 cm/year (from 3.8 to 4.9 cm/year prior to treatment), after a short initial period of deceleration. She remains prepubertal. Recent evaluation by her orthopaedic specialist demonstrated clinical improvement in her bowing without radiographic assessment.

Since burosumab is a new XLHR treatment, the long-term efficacy, risks of adverse effects and screening recommendations are still being determined and thus close monitoring is necessary.^{3 6 7} To date, burosumab has been shown to have superior efficacy to phosphate and calcitriol treatment and good safety profile.^8–10 Improvement in radiographic evidence of rickets is expected after 10 months of therapy. This has been the clinical assessment to date in our patient with no radiographic studies obtained yet to confirm. All other monitoring parameters are based on historic risks on phosphate and calcitriol treatment and potential risks from FGF23 excess and XLH disease.^10–25 We are monitoring her growth velocity, blood pressure and for signs of increased intracranial pressure (headaches, vomiting) every 4 months until 12 years of age (or onset of puberty) and every 6 months thereafter. Fasting serum phosphorus levels were monitored every 4 weeks until the phosphorus levels were in the normal range for 2 months and every 4–6 months thereafter. She undergoes biannual assessments of calcium, intact PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, ALP, creatinine, urinalysis, urinary phosphorus and urinary calcium. Her orthopedist monitors rickets treatment and spine angulation. She will have formal hearing and visual screenings at least every 2 years and regular biannual dental examinations. Her paediatric nephrologist and hypertension specialist manage her hypertension and screens for development of chronic kidney disease.

Discussion

The heterogeneous clinical presentation of XLHR and its low prevalence, relative to physiologic bowing and nutritional rickets, make early and accurate diagnosis challenging unless phosphorus is routinely assessed during evaluations of skeletal dysplasias and impaired growth.¹⁴ Clues to pathological bowing include severe, progressive or persistent bowing after 3 years of age, asymmetric bowing, lateral thrust with ambulation, short stature and history of metabolic disease.

Undiagnosed XLH can result in mineralisation defects and extraskeletal mineral deposits such as enthesopathies with resulting severe and chronic morbidity.¹⁷ In children, it can result in rickets, osteomalacia, muscle weakness and pain with impaired physical functioning, dental abscesses, growth impairment and skull malformations such as craniosynostosis. They may also be at increased risk for Chiari I malformation, spinal stenosis, hypertension and cardiovascular and kidney disease.12 13 15–24

Clinical practice guidelines for the diagnosis and management of XLHR provide a comprehensive framework for accurate diagnosis and follow-up of affected children and adults.^{3 26} However, until all first-line providers (primary care providers, orthopaedic specialists) routinely include serum phosphorus levels in evaluations of poor growth and skeletal deformities suggestive of rickets, the risk for delayed or missed diagnosis remains high.

Our case, combined with the recently reported case of the same PHEX variant (c.1949T>C, p.Leu650Pro) in a Korean toddler with XLH rickets with bilateral bowing, suggests that this rare PHEX variant results in clinically diverse hypophosphatemic rickets with moderate, symmetric or asymmetric skeletal pathology and small stature without dental or extraskeletal involvement to date, other than possibly hypertension. Our treatment outcome supports that this variant causes XLH responsive to burosumab treatment.

The effects of XLH on linear growth may be permanent in up to 60% of children despite correction of phosphate.³ With optimisation of phosphorus levels with phosphate and calcitriol, a 1 SD increase in height has been achieved in a subset of affected children within 2–3 years when treatment was initiated early (by preschool).³ Growth hormone therapy has been attempted in children with continued poor growth but yields inconsistent results and raises concerns for possible aggravation of pre-existing disproportionate stature (ie, increased ratio of trunk to leg length ratio), leading to a lack of clear recommendations for growth hormone use in this population.^27–31 The long-term benefits of burosumab on linear growth and lower limb deformities are unknown.³⁰ Short-term data indicate a possible modest improvement in growth by +0.17 SD per packet insert but longer follow-up of patients is necessary to determine long-term linear growth benefits. Our patient’s growth SDs have not significantly changed with treatment (before treatment Z=−1.54 to −1.65; after treatment Z=−1.65 to −1.69).

In conclusion, we report the second case of this recently reported PHEX gene variant causing XLHR, its clinical correlation to date and the first case of this variant receiving successfully treatment with burosumab. Close monitoring will determine if this variant is linked with further skeletal or extraskeletal comorbidities. We also highlight the importance of obtaining a serum phosphorus level in all initial evaluations of rickets and poor growth, to expedite the accurate and timely diagnosis and prompt treatment and mitigate morbidities of XLH.

Learning points.

• This rare PHEX gene variant (c.1949T>C, p.Leu650Pro) is associated with clinically diverse X-linked hypophosphatemic rickets (XLHR) that can delay diagnosis.

• A serum phosphorus level should always be included with calcium, parathyroid hormone, alkaline phosphatase and 25 hydroxyvitamin D levels, in all investigations of skeletal disorders, and short stature, to avoid delay in diagnosing XLHR and associated morbidity.

• Burosumab treatment appears to be effective for this rare PHEX variant.