Successful treatment with MEK-inhibitor in a patient with NRAS-related cutaneous skeletal hypophosphatemia syndrome.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is caused by somatic mosaic NRAS variants and characterized by melanocytic/sebaceous naevi, eye, and brain malformations, and FGF23-mediated hypophosphatemic rickets. The MEK inhibitor Trametinib, acting on the RAS/MAPK pathway, is a candidate for CSHS therapy. A 4-year-old boy with seborrheic nevus, eye choristoma, multiple hamartomas, brain malformation, pleural lymphangioma and chylothorax developed severe hypophosphatemic rickets unresponsive to phosphate supplementation. The c.182A > G;p.(Gln61Arg) somatic NRAS variant found in DNA from nevus biopsy allowed diagnosing CSHS. We administered Trametinib for 15 months investigating the transcriptional effects at different time points by whole blood RNA-seq. Treatment resulted in prompt normalization of phosphatemia and phosphaturia, catch-up growth, chylothorax regression, improvement of bone mineral density, reduction of epidermal nevus and hamartomas. Global RNA sequencing on peripheral blood mononucleate cells showed transcriptional changes under MEK inhibition consisting in a strong sustained downregulation of signatures related to RAS/MAPK, PI3 kinase, WNT and YAP/TAZ pathways, reverting previously defined transcriptomic signatures. CSHS was effectively treated with a MEK inhibitor with almost complete recovery of rickets and partial regression of the phenotype. We identified "core" genes modulated by MEK inhibition potentially serving as surrogate markers of Trametinib action.

Teriparatide (rhPTH 1-34) treatment in the pediatric age: long-term efficacy and safety data in a cohort with genetic hypoparathyroidism.

BACKGROUND: Hypoparathyroidism is characterized by the absence or inadequately low circulating concentrations of the parathyroid hormone, resulting in hypocalcemia, hyperphosphatemia, and elevated fractional excretion of calcium in the urine. The use of activated vitamin D analogs and calcium supplements represent conventional therapy. Subcutaneous recombinant human parathormone [rhPTH(1-34)] has been proposed as a substitutive treatment, even to avoid side effects of vitamin D and calcium. OBJECTIVE: To assess the long-term safety and efficacy of rhPTH(1-34) in a pediatric cohort of patients with genetic hypoparathyroidism. METHODS: The study is a 9.2-year self-controlled study of six pediatric patients (four males and two females, aged 9.4 ± 5.2) with DiGeorge, hypoparathyroidism-deafness-renal dysplasia (HDR) or autoimmune-candidiasis-polyendocrinopathy-ectodermal-dysplasia (APECED) syndrome, associated with autoimmune intestinal malabsorption in a patient. The presence of clinical signs of hypocalcemia and biochemical parameters, such as calcium, phosphate, alkaline phosphatase in the blood and calcium-creatinine ratio in urine, were compared during conventional treatment and rhPTH(1-34) (teriparatide, 12.5 µg twice daily). RESULTS: The rhPTH(1-34) treatment allowed a reduction, although not always a complete suspension, of calcium supplementation and a slight reduction of calcitriol therapy. The number of tetanic episodes was reduced in four patients during the rhPTH(1-34) treatment. Mean blood calcium, alkaline phosphatase, and phosphate did not significantly change, while a significant reduction of the urinary calcium-to-creatinine ratio (0.55 ± 0.32 vs 0.16 ± 0.09, p = 0.03) was obtained. Renal ultrasound examination showed a worsening in three patients, while it did not change in the remaining three subjects during the follow-up. CONCLUSIONS: In children with syndromic hypoparathyroidism presented here, replacement therapy with rhPTH(1-34) allowed to maintain adequate levels of the calcium and phosphate in the blood, normalize urinary calcium excretion, and reduce tetanic episodes. In patients with low compliance to conventional therapy or intestinal malabsorption, the use of rhPTH(1-34) could be considered, also to reduce the side effects of treatment with vitamin D and calcium.

Iatrogenic acute pancreatitis due to hypercalcemia in a child with pseudohypoparathyroidism.

Pancreatitis due to hypercalcemia is very rare in children, and its pathogenetic role is still debated. The following report describes a case of acute pancreatitis secondary to hypercalcemia in a 6-year-old boy with pseudohypoparathyroidism treated with calcium and vitamin D. Pseudohypoparathyroidism is characterized by parathormone (PTH) resistance, high PTH levels and hypocalcemia which need to be corrected with calcium and vitamin D supplementation. The patient was admitted for severe abdominal pain and vomiting associated with high plasma amylase, lipase and calcium levels. Hypercalcemia due to vitamin D and calcium overtreatment was probably responsible for the acute pancreatitis in this case. High serum calcium levels seem to sensitize patients to pancreatitis, even if the mechanism through which it happens is not completely understood. Moreover, the importance of concomitant predisposing factors, either acquired or especially genetic, needs to be further defined. Even though a rare occurance in childhood, hypercalcemia should be considered as a cause of pancreatitis and it should be examined together with the other etiologies that may contribute to the development of this disease.