A 14-year-old girl presented in OPD at the Civil Hospital Karachi with complaints of generalized body weakness, bilateral shoulder and knee pain, and difficulty walking since 6 years of age. The child was known to have a global developmental delay as she started walking after 2 years of age and hasnot started menstruating yet. Her family history was unremarkable, and both of her parents had normal achievement of milestones. The patient had no history of headaches, trauma, visual difficulty, oral ulcers, alopecia, rash, photosensitivity, dysphagia, polyuria, polydipsia, numbness, paresthesia, and anosmia. She had been born at 38 weeks of gestation by emergency C-section due to obstructed labor due to the malposition of the baby. Her birth weight was 3500 grams, and there had not been any initial neonatal concerns. She achieved her milestones late and had a positive history of fits at 3 years of age, for which she has been taking syrup sodium valproate 6.25mg/kg (Normal dosage = 20-40mg/kg) for 10 years. On examination, she appeared to have a short stature with height of 115 cm with a weight of 20 kg and BMI of 15 kg/m2 suffering from primary amenorrhea, accompanied by normal external genitalia but poor breast and pubic hair development (Tanner stage 2). She had prominent tender costochondral junction and scoliosis at the back with wrist widening bilaterally upper limbs and bowing of knees (Figure 1),but no frontal bossing or deformity of the chest was present.She was bed-bound due to contractures and restricted movement in her shoulder and knee joints. Knee joints were tender without any discoloration, warmth, or swelling. The neurological assessment revealed decreased bulk and power with increased tone in all four limbs and normal reflexes. All the cranial nerves were intact. Laboratory findings revealed: hypophosphatemia (1.4 mg/dL), proteinuria (3+), glycosuria (+2), blood sugar of 111mg/dl, reduced percent tubular reabsorption of phosphate (TRP) (72 %; normal > 80 %) and tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR) (1.78; normal 2.8-6.2) showing impairment of proximal renal tubule. The patient had borderline serum potassium (3.8 mEq/L), hypomagnesaemia (1.6mg/dl), hypouricemia (1.1mg/dl), and normal anion gap metabolic acidosis (pH 7.0, pCO2 30.5 mmHg, pO2 115mmHg, base excess 5.8 mmol/L, serum bicarbonate 18 mmol/L). A marked increase in alkaline phosphatase (ALP) levels (2180IU/L) and 25-Hydrioxyvitamin D3 (121 ng/ml) with normal corrected calcium (9.52 mg/dl) and serum parathyroid (PTH) levels (36.90 pg/ml) was noticed. Despite the inadequate dosage, the valproic acid blood level was normal (70.8 mcg/mL; normal value = 50-100 mcg/mL). Tests within normal limits included complete blood count (CBC), ceruloplasmin, audiometry, and urinary mercury, arsenic, and lead. Serum and urinary data on admission are provided in Table 1.
The eye exam neither revealed cysteine crystals nor Kayser-Fleischer rings. X-ray skeletal survey (Figure 2) showed markedly reduced bone density, especially in the pelvis and long bone, funnel-shaped pelvis with protrusio acetabula bilaterally, widened costochondral junction with a looser zone in some ribs, and multiple partially healed fractures in the proximal humerus, the proximal ulna, distal femur, and proximal tibia bilaterally, suggesting diagnoses of hypophosphatemic rickets. U/S abdomen revealed normal-sized kidneys without any calculi, mass, and hydronephrosis, while U/S pelvis revealed a hypo-plastic uterus with normal-sized ovaries (Figure 3). Hormonal Assay suggested a picture of HH showing low serum FSH (1.04 mIU/ml), LH (< 0.07 mIU/ml), androstenedione (< 0.30 ng/ml), and DHEASO4 levels (16.40 ug/ml; normal value 36-130 ug/ml) while rest of the pituitary hormones were in normal ranges. We also performed an Electroencephalogram (EEG), which came out normal according to the age and state of the patient. MRI suggested a normal scan with normal-sized pituitary gland with no evidence of hypo or hyperintense lesion in the basal ganglia.
In view of the clinical features (bone pain, wrist widening, costochondral tenderness, amenorrhea), skeletal survey, U/S, EEG, MRI, and laboratory results (hypophosphatemia, glycosuria, aminoaciduria, decreased TRP%, TmP/GFR, reduced FSH, LH, estrogen,) impression of Fanconi syndrome causing hypophosphatemic rickets co-existing with hypogonadotropic hypogonadism was made. However, a certain cause for Fanconi syndrome and HH could not be identified. No genetic testing was performed to confirm the diagnosis. The patient was started with oral medication, including sodium phosphate (joule’s solution), magnesium, calcium, and vitamin D3 supplements.