Editorial note: In this case we have questioned the diagnosis the authors have made. The idea of this is not to criticize the efforts of the authors, but to point out an obvious flaw or error made in the diagnosis in this case. If you disagree with our explanation please feel free to send me an email on endocrinecases@gmail.com

A 11 years old girl of a consanguineous parents belonging to a low socioeconomic status, hailing from Nazirabazar, Dhaka, was admitted at Dhaka Medical College Hospital on 07/03/07 with inward bending of both legs for last 4 years, not gaining height in comparison to other children of same age and dental caries for 2-3 years.


She had no history of polyuria, dysuria, jaundice, recurrent chest infections or recurrent attacks of diarrhoea and not on long term anticonvulsant drugs.


Q  What is the importance of Polyuria in case of Rickets ?


  • Polyuria with rickets is suggestive of Renal tubular acidosis, Barrter’s syndrome and certain cases of CKD.


Birth history was uneventful and was partially immunized as per EPI schedule. After birth she was predominantly breast fed for only 5 successive months and currently she is on family diet, i.e., rice, vegetable, fruits but low quantity of fish, meat, milk and egg as they are unable to afford those.


Q  Are any of these good sources of vitamin D ?


  • Since this case is from Bangladesh, food fortification status of general foods is not known.
  • However, fatty fishes are good source of vitamin D , so the child may be receiving some vitamin D


Though her milestones of development were normal, her linear growth and also weight were not satisfactory as compared to that of other children of her age. Exposure to sunlight was adequate as she used to play along with other children in open air. Her father did not have the same disease and died of kidney disease two years back. Her mother and sibs are healthy


On examination, her pulse was 40/min, BP-100/60 mm Hg and temperature was normal.

Anthropometric measurement revealed height – 108 cm (74.2% of

NCHS median), weight – 18 kg (55.3% of NCHS median) and weight for height – 98.5% of NCHS median.

Both wrist and knee joints were widened , knocked knee was obvious on standing.

The chest examination demonstrated pegion chest deformity, mild rachitic rosary but there was no Harrison’s sulcus or other deformities of the limbs or joints.

However, dental caries were present in both upper and lower molar teeth


Radiologically, cupping, fraying and widening of growing lower ends of femur as well as radius and ulna, thinning of cortex and generalized osteopenia were revealed.


Q  What are X-ray features of Hypophosphatemic rickets ?


  • Hypophosphatemic rickets will show metaphyseal changes like widening and splaying, but calcipenic changes like fraying and osteopenia will not be seen.
  • Sclerosis may be seen.


Laboratory investigations showed TC of WBC 8000/cmm, DC: polymorph 60%, lymphocyte 37%, monocyte 2%, basophil 1%, eosinophil 2%. Total platelet count was within normal range. Anisocytosis and poikilocytosis of RBC and mature WBC were showed in peripheral blood film.


Biochemical investigations showed near serum calcium (Ca++) level of 8.4 mg/dL (N: 8.8-10.8 mg/dL), serum phosphate 2.5 mg/dL (N: 4-7 mg/dL), while alkaline phosphatase was 630 IU/L which was much higher than normal range (N: 115-431 IU/L). Serum creatinine was 0.8 mg/dL and SGPT 40 IU/dL. The parathyroid hormone level was within normal limit 11 pg/mL (N: 7-53 pg/mL). Urine examination showed phosphaturia and its level was 24.5 mg/dL. Urinary creatinine was 22.5 mg/dL (N: 15-20mg/dL). As there is no definite range of the urinary phosphate level of 11 years old girl, tubular reabsorption of phosphorus (TRP) was calculated

The TRP was 68% (N: 78-98%) which confirmed loss of excess phosphate through urine. However, serum 1-α-hydroxylase level could not be done. All parameters of electrolytes were normal. Benedict’s test showed no glucosuria.


Both the clinical features and laboratory parameters were consistent with familial hypophosphatemic rickets.


Q  Do you agree with the diagnosis ?


  • No
  • Infact in my opinion the diagnosis in this case is most likely nutritional rickets due to vitamin D deficiency

Q  What is the most important investigation that has been missed out in this analysis ?


  • A 25-hydroxy- vitamin D level is not done.


Q  What are the points in favour of this being a nutritional rickets ?


  • Osteopenia in X-ray is a features of nutritional rickets and it is NOT seen in XLRH
  • 25(OH) vitamin D is not obtained
  • Serum calcium levels are low. XLRH patients generally have normal serum calcium levels.

Q  if it is nutritional rickets, what explains the phosphate wasting ?


  • Vitamin D deficiency typically produces secondary hyperparathyroidism.
  • Increase PTH typically causes phosphate loss.
  • The increase TRP can be very well explained by the secondary hyperparathyroidism.


Q  You say it is secondary hyperparathyroidism , but the PTH levels is normal !


  • PTH assay depends much on the transport.
  • Improper transport of sample in cold chain can lead to reduction in PTH values and hence false low PTH.
  • This is a well known fact and activation of thrombin is responsible for lowering of PTH values in the sample.
  • Hence I believe that the PTH levels were false low.


Both the clinical features and laboratory parameters were consistent with familial hypophosphatemic rickets. So, she was treated with Joulie solution, an oral phosphate suspension made up of sodium phosphate (136 gm/L) and phosphoric acid (58.8 gm/L)5 1.5 tsf every 4 hourly. Active form of vitamine D (1-25 dihydroxy cholecalciferol) was also given in the form of Dicatrol capsule (0.25mcg) 6 hourly.


Along with treatment we consulted with orthopaedic department. She was advised to continue the treatment and for regular follow up. After 2 weeks of treatment with oral phosphate and dicatrol, significant radiological improvement was documented. Genetic counseling was also done. As the disease is X-linked, the defective gene may come either from father or from mother. Unfortunately, the genetic study is not possible in Bangladesh. As the father died two years back, there is no chance to have any more children.


Q  So if the diagnosis was probably incorrect, why did the child respond to treatment ?


  • The child was given active vitamin D supplementation.
  • If the child truly has vitamin D deficiency as we are thinking, she would have responded to active vitamin D supplementation as well.

Learning objective

  • When dealing with a case of rickets, it is always important to rule out common things first. Vitamin d deficiency (nutritional rickets) is far more common compared to other forms of rickets and must always be ruled out before further investigations are considered.
  • Vitamin D deficiency with secondary hyperparathyroidism ALSO causes loss of urine phosphate and hence TRP will be reduced in such cases.

An interesting case of Hypercalcemia of malignancy.

Original case by Cheng Cheng, Jose Kuzhively, and Sanford Baim

A 26-year-old African American male, with no significant past medical history, presented to the emergency department in early November 2016 with complaints of fever, malaise, 18 lb weight loss over 2 weeks, and multiple neck masses

Q  What is definition of clinically significant weight loss ?

>5% weight loss over period of 6-12 months

Q  What is Cachexia and Sarcopenia ?

  1. Sarcopenia- reduction in muscle mass, strength or function with or without weight loss- eg: Sarcopenia can also occur in obese
  2. Cachexia= weight loss + loss of muscle mass

Q  Enlist the causes of unintentional weight loss ?


  1. Vascular- CCF- Cardiac cachexia
  2. Infective- HIV, tuberculosis
  3. Neoplasm – malignant – GI and Non GI malignancies
  4. Drugs
  5. Autoimmune – Lawrence syndrome- acquired generalized lipodystrophy
  6. E- Endocrinopathies- see next page
  7. Non maligant GI disorder
  8. Pulmonary disorder- COPD, Pulmonary chachexia
  9. Pyschiatric problems- anorexia nervosa, depression
  10. Neurological disorders
  11. Rheumatological disorders
  12. CKD
  13. CLD

Q  What are endocrine causes of weight loss ?

  1. Adrenal insufficiency
  2. Hyperthyroidism
  3. Type 1 diabetes
  4. Glucogonoma
  5. Pheochromocytoma
  6. Endocrine malignacies

Medications prior to admission consisted of cyclobenzaprine, meloxicam, tramadol, and recreational use of marijuana. Initial imaging revealed an anterior mediastinal mass with intrathoracic lymphadenopathy, bilateral pulmonary nodules, and spine lesions on CT

Q Name some important causes of anterior mediastinal mass ?

  1. Thymic mass- thymic enlargement or thymic carcinoma
  2. Lymphoma
  3. Substernal/ ectopic goiter
  4. Germ cell tumor- mediastinum is the most common site for extragonadal germ cell tumors

Q Which endocrine related condition must be ruled out in case of mediastinal germ cell tumors ?

  • Klienfelter syndrome

Physical exam demonstrated bilateral supraclavicular lymphadenopathy that was tender to palpation, pain on palpation of the cervical and lumbar spine, and normal neurological exam.

Labs on admission were notable for corrected total calcium (Calc) of 15.1 mg/dL, ionized calcium (iCa) of 1.59 mg/dL (ref: 0.95–1.32 mg/dL), PTH of 4.8 pg/mL (ref: 8–85 pg/mL), phosphorus (Phos) of 2 mg/dL (ref: 2/5–4.6 mg/dL), creatinine of 1.16 mg/dL (ref: 0.75–1.2 mg/dL), and blood count with no atypical cells seen on the differential

Q What is your interpretation of the cause of hypercalcemia in this case ?

  • This is hypercalcemia with clearly suppressed PTH.
  • This is most certainly a case of PTH independent hypercalcemia.
  • Q What PTH value suggest PTH independent hypercalcemia ?
  • Typically PTH <20 pg/ml generally suggest PTH independent hypercalcemia ?

Aggressive IV hydration with normal saline at a rate of 250 cc/hr was promptly started and maintained throughout this admission with administration of pamidronate 90 mg on hospital day 2.

Q Give the proposed line of treatment for severe hypercalcemia ?

  • Injection Normal Saline
    • 250 ml/hr for 2 hrs followed
    • 150 ml/hr for next 20 hrs
    • 100 m/hr for next 24 hrs
    • Diuretics not used routinely and given only if the patient develops fluid overload or has congestive cardiac failure.
    • TEST DOSE : 4 units / kg subcutaneously stat (Approximately 200 units) – repeat serum calcium after 3 hrs. If there is no fall in calcium or patient has reaction to calcitonin then it is not continued any more – If the response is seen then give a dose of 4 units/kg subcutenously every 12 hrs
    • Increase the dose to 8 units/kg every 12 hrs if little response seen in 1-2 days. The dose and frequency may be further increased upto maximum dose of 8 units/kg every 6 hrs
    • Effect seen for generally 3-5 days only . After this tachyphylaxis to calcitonin often develops
    • Patient may develop nausea and vomiting with calcitonin. Inj EMSET (ondensatron) may be given sos if nausea/ vomiting develops
  • Inj Zolendronic acid (Inj NATZOLD)
    • Given on first or second day itself
    • Avoided if Parathyroid surgery is planned within 1-2 days
      • 150 ml of Normal saline f/b
      • Inj NATZOLD 5 mg (100ml) infusion over 15 min f.b
      • 150 ml of normal saline
    • W/f fever, joint pain etc for 24 hrs- if this develop NSAIDs may be given
    • Take 2-5 days for onset of effect
    • Effect lasts for 2-8 weeks. In patient with malignancy associated hypercalcemia which cannot be treated otherwise- the dose may be repeated after 1 month
    • 30 mg OD starting dose ( Maximum of 90 mg QID)
    • Given as alternate to Zolendronate in patients with hyperparathyroidism in whom surgery is planned
  • Hemodialysis
    • Considered in patients with acute renal failure and/or Serum Calcium >18 mg/dl with neurological symptoms
  • Denusomab
    • Indications
      • Hypercalcemia with renal failure
      • Hypercalcemia refractory to bisphosphonates
    • Dose
      • Inj XGEVA – 120 mg subcutaneously weekly for 4 weeks followed by monthly
    • Glucocorticoid
      • Inj Hydrocortisone (Inj Effcorlin) 100 mg IV /8hrly
      • Or if patient takes orally T. Prednisolone ( Wysolone) 40 mg per day
      • Given in case of vitamin D toxicity or granulomatous disease associated hypercalcemia
    • Once the patient becomes better and the etiology for hypercalcemia not treated then patient advice
      • Good oral hydration- 6-8 glasses of water /day
      • Low calcium diet
      • Avoid prolonged bedrest
      • Avoid thiazide diuretics
    • Check serum calcium and serum creatinine daily

Additional studies included supraclavicular lymph node and bone marrow biopsies consistent with Epstein-Barr virus positive metastatic undifferentiated, non-keratinizing, lymphoepithelioma-like carcinoma of thymic origin. After undergoing staging with additional imaging, the patient completed his first cycle of chemotherapy with cisplatin, doxorubicin, and cytoxan in the next 2 weeks. His Calc decreased to 10.5 mg/dL at the time of discharge.

Approximately 2 weeks after discharge, the patient was readmitted for a second admission with increasing somnolence. Laboratory analysis disclosed Calc of 15.4 mg/dL and iCa of 1.72 mg/dL for which IV hydration with normal saline at 250 cc/hr was initiated followed by pamidronate 90 mg and calcitonin 300 U with improvement of iCa to as low as 1.16 mg/dL.

PTH-related peptide (PTHrP) and 1,25-dihydroxyvitamin D (calcitriol) were sent during this admission but results were not available.


Q Why did they send 1,25 dihydroxyvitamin D ?

    • Granulomatous disease increase produce of 1 alpha hydroxylase enzyme leading to increase 1,25 dihydroxyvitamin D levels.

Q What is the differene in actions of PTHrP and PTH in relation to calcium and phosphate ?

    • PTHrP does not increase 1,25 dihydroxy vitamin D, however it does cause phosphaturia.
    • Hence in case of a PTHrP producing tumor the typical biochemical picture is as follows:
  1. Serum calcium- high
  2. Serum phosphate- low
  3. PTH- low
  4. 1,25 dihydroxyvitamin D – low

Repeat MRI of the entire spine noted new hyperintense metastatic lesions.

Over the ensuing 3 days, iCa slowly increased to 1.46 mg/dL and required administration of zoledronate 4 mg resulting in normalization of iCa between 1 and 1.1 mg/dL for the rest of the admission (Figure 1). The patient subsequently began cycle 2 of cisplatin, doxorubicin, and cytoxan which was completed prior to discharge with a plan to initiate denosumab as an outpatient

During outpatient follow-up and 5 days after discharge, a rapid rebound in hypercalcemia occurred with Calc of 12.6 mg/dL and iCa of 1.46 mg/dL, requiring administration of denosumab 120 mg which decreased iCa to 1.25 mg/dL (Figure 1). A second dose of denosumab 120 mg was given 1 week later with concurrent Calc of 12.7 mg/dL.

Q What percentage of calcium is ionized  ?

  • 50% of calcium is in ionized form
  • 40% – protein bound
  • 10% – bound to inorganic acids
  • Q In which conditions is measurement of ionized calcium important ?
  1. Acid base disorder
  2. Hypoalbuminemia
  3. CKD

Q How is mmol/l converted to mg/dl ?

  • Mmol/lt = (mg/dl x 10 ) / mol wt

Q What is the conversion for calcium ?

  • Mol wt is 40 and valence is 2
  • Mg/dl divide by 4 = mmol/lt

Q How is calcium adjusted for albumin ?

  • Correct calcium = measured calcium + 0.8 x (4- measured serum albumin)
  • Total calcium falls by 0.8 mg/dl for every 1 g/dl fall in albumin

Q What happens in patients with multiple myeloma ?

  • They have pseudohypercalcemia
  • This is because of increase of calcium bound to myeloma cells
  • Since MM itself may be associated with increase calcium, it is important to use ionized calcium for the same

Q How do acid base disorders change ionized calcium ?

  • Alkalosis – there is increase binding of calcium to albumin thus reducing ionized calcium

Q What is the effect of PTH on ionized calcium ?

  • PTH sepearates calcium from albumin and increases the ionized calcium

Q What is the effect of phosphate on ionized calcium ?

  • Acute hyperphosphatemia will reduce the ionized calcium
  • This is because it will bind with the ionized calcium
  • Gradually the total calcium will also drop

Q Why is total calcium and calcium calculations not reliable in patients with CKD ?

  1. CKD patients have metabolic acidosis hence higher ionized calcium
  2. The albumin correction formula overestimates the ionized calcium in CKD patients

Hence in CKD patients it is preferable to measure ionized calcium directly

Q What is the normal ionized calcium value in adults ?

  • In adults normal values of ionized calcium is  64 to 5.28 mg/dl
  • This is equivalent to 1.15 to 1.3 mmol/ (approx)

One month later, the patient was readmitted with altered mental status with Calc of 13.6 mg/dL, iCa of 1.53 mg/dL, Phos of 1.6 mg/dL, and normal renal function. The patient received prompt administration of IV hydration with normal saline and pamidronate 90 mg. Although iCa level decreased to 1.3–1.4 mg/dL within 2 days, it rebounded over the next 24–48 hours to 1.64 mg/dL, requiring further administration of zoledronate 4 mg

At this time, it was noted that his 1,25-dihydroxyvitamin D level from the previous admission was elevated at 131 pg/mL (ref: 18–64 pg/mL) and PTHrP at 27 pg/mL (ref: 14–27 pg/mL). Methylprednisolone 60 mg per day was subsequently instituted over the next 2 days with decrease in iCa level to 1.3–1.4 mg/dL

However, the patient continued to clinically deteriorate, despite iCa being maintained at 1.3–1.4 mg/dL (Figure 1) with development of multiorgan failure, and he expired shortly after. It is noteworthy that the third admission repeated PTHrP and calcitriol levels that returned to the medical record posthumously were 58 pg/mL and 499 pg/mL, respectively.

Q What will you suspect in a case of hypercalcemia associated in malignancy where PTHrP and 1,25 dihydroxyvitamin D are normal, PTH is suppressed and there is no evidence of osteolytic metastasis ?

  • Think of Hypercalcemia of malignancy associated with cytokine/chemokine associated bone resorption.

Q Enlist the etiologies for hypercalcemia of malignancy ?

  1. Local osteolytic hypercalcemia – due to osteolytic metastasis
  2. Increase 1,25 dihydroxy vitamin D production
  3. Ectopic PTHrP production
  4. Ectopic PTH production
  5. Cytokine/chemokine associated hypercalcemia


Q What is the possible etiology of hypercalcemia in this case ?

  • In this case multiple reasons for hypercalcemia may be present either togather or evolving over time.
  • The patient has
  1. Metastasis to the bones which may have been osteolytic (“Repeat MRI of the entire spine noted new hyperintense metastatic lesions)
  2. Increase 1,25 dihydroxyvitamin D levels due to tumor producing 1 alpha hydroxylase.  (it was noted that his 1,25-dihydroxyvitamin D level from the previous admission was elevated at 131 pg/mL (ref: 18–64 pg/mL)
  3. Ectopic PTHrP production (It is noteworthy that the third admission repeated PTHrP and calcitriol levels that returned to the medical record posthumously were 58 pg/mL and 499 pg/mL, respectively)
  4. Hypercalcemia secondary to cytokine / chemokines.

Learning objective

  • In a patient with hypercalcemia of malignancy , multiple causes of hypercalcemia may exist in the same patient.
  • Denusomab is useful in case of hypercalcemia refractory to bisphosphonate therapy.


ENDOCRINE ROUNDS CASE 4 -Hypopituitarism with Osteoporosis

A 79 year old male was diagnosed to have non-functioning pituitary adenoma compressing the optic chiasma in 2011. Patient was subsequently operated in 2011. Anterior pituitary assessment post-surgery was not done and patient was on some anterior pituitary hormone replacement on and off. Patient developed a fracture neck femur on minimum trauma. He was admitted for the same and endocrinology consultation was sought for the anterior pituitary assessment and management of osteoporosis.
Patient had a residual pituitary mass and postoperative changes in MRI pituitary. The mass was found infiltrating into the left cavernous sinus and engulfing the left ICA.


[FIG 4.1 AND 4.2]

The pituitary evaluation showed
1. Low T3, T4 and TSH- Suggestive of central hypothyroidism
2. Low testosterone and FSH/LH
3. Normal Prolactin
4. Serum cortisol – 7 mcg/dl- post stimulation of 12 mcg/dl
5. GH deficiency
6. No evidence of Diabetes insipidus
Hence the patient is having panhypopituitarism following the pituitary surgery. Patient was started on glucocorticoid and thyroid hormone replacement.

was started on glucocorticoid and thyroid hormone replacement.

The questions are

Q What is the Hardy grading of the Pituitary mass described above ?
Since it involves the cavernous sinus it would be classified as Hardy Grade E

Q. Does the patient need a DEXA scan for evaluation of osteoporosis ? Is treatment for osteoporosis indicated in this patient ?
Men with hip or vertebral fracture with low trauma with a clear risk of having osteoporosis as in this case donot require DEXA scan for BMD evaluation and the patient can be presumed to have osteoporosis.

Q. Deficiency of which hormones in this can may lead to osteoporosis ?
GH and Testosterone deficiency are the reasons for osteoporosis.

Q. What would be the ideal treatment for osteoporosis and prevention of further fracture in this patient ?

1. I would consider replacing both testosterone and GH in this patient (if there are no contraindications to either). There are recent studies which have shown benefit of GH on improving bone mineral density in adults with GHD
2. Since the fracture is recent, I would withhold bisphosphonate for now. Whether to use bisphosphonate or not on follow-up is controversial.
3. Overtreatment with glucocorticoids and thyroid hormones needs to avoided.
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