POSSIBLE PSEUDOHYPOPARATHYROIDISM 10/1/2015
QUESTION-I have a 15 year old boy who presented with severe generalized Acanthosis nigricans, strong family history(both parents) of early (20's) onset Type 2 DM. He height was between 5th-10th centile, he was stocky in appearance, not exactly obese, but over weight, with abdominal obesity and buffalo hump. He was a secondary school drop out with a low IQ and a dysmorphic face not resembling either mother or father.
Investigations revealed Severe Insulin resistance, OGTT was normal, and he had mild-mod vitamin D eficiency. The only other abnormal test was elevated serum Phosphorus ( 7mg/dl). S.Calcium and ALP were normal.
I started him on Metformin and life style changes , given the very high insulin levels and strong family history of Type2DM. He responded excellently with much improved acanthosis and his body habitus became much leaner. I also supplemented good doses of Vitamin D.
However when the serum Phosphorus was repeated, it was consistently high ( 8, 11 mg/dl), in the presence of absolutely normal S calcium. Further tests revealed his PTH to be elevated ( 113 pg/ml), normal USG of kidneys, Fe PO4 was only 0.4% (low). No e/o subcutaneous calcifications so far.
My doubt is that, how aggressively should we be treating the Serum phosphorus value, when the child is asymptomatic, and is having well preserved calcium levels? Thanks, Dr Sirisha Kusuma B, Hyderabad
RESPONSE- Your case was forwarded to me per Dr DeGroot. It is curious and I do not believe is straightforward. Certainly with the serum PTH level elevated, and apparently very little phosphate excreted in the urine, the first consideration here would be PTH resistance at the kidney or a variant of pseudohypoparathyroidism. However the absence of a decrease in the serum calcium is curious in this setting, and the Free excretion of phosphate is even lower than customary for that condition in my experience.
I would consider that there is a defect in the phosphate regulating hormone, FGF23, in this setting and that perhaps this child has a variant of hyperphosphatemic tumoral calcinosis. This disorder can result from loss of function mutations in GALNT3 (which is necessary for processing of FGF23) and from loss of function mutations in FGF23 itself. There is one case that has been found in the setting of a mutation in klotho, the FGF23 co-receptor. 1,25 dihydroxyvitamin D levels are often generous in this condition as well. C-terminal FGF23 may be elevated, normal , or low, but the intact FGF23 is low in most cases.
Several tests may shed light on this. I would sample family members, and perform FePO4 (or TRP and TMP/GFR) as well as serum Ca, P, and 1,25 dihydroxyvitamin D in him, (and siblings and parents if possible). Assay of FGF23 in both a C-terminal assay and a "sandwich" assay detecting only the intact species, would be very helpful as well. Of course normal renal function should be documented in all, which I believe you have probably already done. Calcifications may be deeper in this condition than the subcutaneous heterotopic bone seen in pseudohypoparathyroidism. Amorphous precipitate of calcium phosphate may precipitate in muscle and joint areas, as well as the pelvis. You may have clues by physical examination in this regard, but if the diagnosis holds up you may want to survey radiographically for involved sites. Skeletal findings with the GALNT3 mutation can be variable but mild hyperostosis may be evident of the long bones, as well.I hope this is of use; good luck and please let us know what our evaluation reveals. Thomas Carpenter, Yale Medical School, New Haven.