Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, autosomal recessive disorder caused by mutations in the SLC34A3 gene that encodes the renal sodium-dependent phosphate cotransporter 2c (NaPi-IIc). It may present as intermittent mild hypercalcemia which may attract initial diagnostic attention but appreciation of concomitant hypophosphatemia is critical for consideration of the necessary diagnostic approach. A 21-year-old woman was assessed by adult endocrinology for low bone mass. She initially presented age two with short stature, nephrocalcinosis and mild intermittent hypercalcemia with hypercalciuria. She had no evidence of medullary sponge kidney or Fanconi syndrome and no bone deformities, pain or fractures. She had recurrent episodes of nephrolithiasis. In childhood, she was treated with hydrochlorothiazide to reduce urinary calcium. Upon review of prior investigations, she had persistent hypophosphatemia with phosphaturia, low PTH and a high-normal calcitriol. A diagnosis of HHRH was suspected and genetic testing confirmed a homozygous c.1483G>A (p.G495R) missense mutation of the SLC34A3 gene. She was started on oral phosphate replacement which normalized her serum phosphate, serum calcium and urine calcium levels over the subsequent 5 years. HHRH is an autosomal recessive condition that causes decreased renal reabsorption of phosphate, leading to hyperphosphaturia, hypophosphatemia and PTH-independent hypercalcemia due to the physiologic increase in calcitriol which also promotes hypercalciuria. Classically, patients present in childhood with bone pain, vitamin D-independent rickets and growth delay. This case of a SLC34A3 mutation illustrates the importance of investigating chronic hypophosphatemia even in the presence of other more common electrolyte abnormalities.
Hypophosphatemia is an important diagnostic clue that should not be ignored, even in the face of more common electrolyte disorders.
HHRH is a cause of PTH-independent hypophosphatemia that may also show hypercalcemia.
HHRH is a cause of hypophosphatemic nephrocalcinosis that should not be treated with calcitriol, unlike other congenital phosphate wasting syndromes.
Some congenital phosphate wasting disorders may not present until adolescence or early adulthood.
M ClementeDepartment of Pediatric Endocrinology, Children’s University Hospital Vall Hebron, Barcelona, Spain Autonomous University of Barcelona, Barcelona, Spain Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
L CastañoCentre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain Endocrinology and Diabetes Research Group, BioCruces Health Research Institute, UPV-EHU, CIBERDEM, Cruces University Hospital, Barakaldo, Spain
A Moreno-GaldóAutonomous University of Barcelona, Barcelona, Spain Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain Department of Pediatrics, Children’s University Hospital Vall Hebron, Barcelona, Spain
D YesteDepartment of Pediatric Endocrinology, Children’s University Hospital Vall Hebron, Barcelona, Spain Autonomous University of Barcelona, Barcelona, Spain Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
A CarrascosaDepartment of Pediatric Endocrinology, Children’s University Hospital Vall Hebron, Barcelona, Spain Autonomous University of Barcelona, Barcelona, Spain Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results.
Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity.
Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed.
Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients.
Treatment has been well tolerated and no side effects have been detected.
Christine P BurrenDepartments of Paediatric Endocrinology and Diabetes NIHR Biomedical Research Unit in Nutrition, Diet & Lifestyle, University Hospitals Bristol NHS Foundation Trust, Education Centre, Bristol, UK
This case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new insights on hypothalamic–pituitary–gonadal (HPG) axis and testicular function abnormalities in the multisystem disorder of Lowe syndrome. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare disorder characterised by eye abnormalities, central nervous system involvement and proximal renal tubular acidosis. There are a handful of reports of pubertal delay, infertility and cryptorchidism in Lowe syndrome. Biochemistry aged 72 h: testosterone 6.4 nmol/L, LH <0.5 IU/L and FSH <0.5 IU/L. Gonadotropin-releasing hormone stimulation test identified significantly raised baseline LH = 45.4 IU/L (contrasts with earlier undetectable LH), with a 20% increase on stimulation, while baseline FSH = 4.3 IU/L with no increase on stimulation. Day 14 HCG stimulation test produced an acceptable 50% increase in testosterone. The constellation of further abnormalities suggested Lowe syndrome: hypotonia, bilateral cataracts (surgical extraction and intraocular lens implantation) and renal tubular acidosis (microscopic haematuria, hypercalciuria, proteinuria, generalised aminoaciduria, hypophosphataemia and metabolic acidosis). DNA sequencing identified de novo hemizygous frameshift mutation OCRL c.2409_2410delCT in exon 22. Interpretation of initial and repeat GnRH and HCG testing indicates the likelihood of testicular failure. Partial testicular descent occurred but left orchidopexy was required. Improving long-term gonadal function in Lowe syndrome assumes increased importance for current cohorts as advances in renal replacement therapy have greatly improved life expectancy. Noting HPG axis abnormalities in Lowe syndrome in infancy can identify cases requiring increased surveillance of pubertal progress for earlier detection and management.
Clinical endocrine problems in Lowe syndrome has been reported, but has focused on abnormalities in adolescence and young adulthood: pubertal delay and infertility.
We present an infant with isolated LH elevation at baseline and on GnRH stimulation testing who also had bilateral impalpable testes.
Early testing of the HPG axis in patients with Lowe syndrome may help predict gonadal abnormalities from a younger age, which will enhance the overall case management into adolescence.
Marisa M FisherDivision of Pediatric Endocrinology, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, 705 Riley Hospital Drive, Room 5960, Indianapolis, Indiana, 46220, USA
Susanne M CabreraDivision of Pediatric Endocrinology, Department of Pediatrics, Medical College of Wisconsin, Children's Hospital of Wisconsin, 9000 W. Wisconsin Avenue, PO Box 1997, Milwaukee, Wisconsin, 53201, USA
Erik A ImelDivision of Pediatric Endocrinology, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, 705 Riley Hospital Drive, Room 5960, Indianapolis, Indiana, 46220, USA Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 541 North Clinical Drive, Indianapolis, Indiana, 46202, USA
Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder caused by inactivating calcium-sensing receptor (CASR) mutations that result in life-threatening hypercalcemia and metabolic bone disease. Until recently, therapy has been surgical parathyroidectomy. Three previous case reports have shown successful medical management of NSHPT with cinacalcet. Here we present the detailed description of two unrelated patients with NSHPT due to heterozygous R185Q CASR mutations. Patient 1 was diagnosed at 11 months of age and had developmental delays, dysphagia, bell-shaped chest, and periosteal bone reactions. Patient 2 was diagnosed at 1 month of age and had failure to thrive, osteopenia, and multiple rib fractures. Cinacalcet was initiated at 13 months of age in patient 1, and at 4 months of age in patient 2. We have successfully normalized their parathyroid hormone and alkaline phosphatase levels. Despite the continuance of mild hypercalcemia (11–12 mg/dl), both patients showed no hypercalcemic symptoms. Importantly, patient 1 had improved neurodevelopment and patient 2 never experienced any developmental delays after starting cinacalcet. Neither experienced fractures after starting cinacalcet. Both have been successfully managed long-term without any significant adverse events. These cases expand the current literature of cinacalcet use in NSHPT to five successful reported cases. We propose that cinacalcet may be considered as an option for treating the severe hypercalcemia and metabolic bone disease found in infants and children with inactivating CASR disorders.
NSHPT due to mutations in the CASR gene occurs with hypercalcemia and metabolic bone disease, but not always with severe critical illness in infancy.
NSHPT should be considered in the differential diagnosis for a newborn with a bell-shaped chest, osteopenia, and periosteal reactions.
Neurodevelopmental consequences may occur in children with hypercalcemia and may improve during treatment.
Calcimimetics can be used to successfully treat the pathophysiology of NSHPT directly to control serum calcium levels.
A 53-year-old male presented with recurrent calcium oxalate kidney stones as a first sign of underlying acromegaly, which vanished when his acromegaly was controlled. The exact mechanism behind hypercalciuria and urolithiasis in acromegaly is not yet clear. By discussing this case, a short overview of the pathophysiology of hypercalciuria in acromegaly and practical insights are given.
Hypercalciuria is a common finding in acromegaly.
There are only few reports describing hypercalciuric kidney stones in acromegaly.
We assume that in acromegaly there is a primary role of IGF1-mediated, PTH-independent increase in calcitriol synthesis resulting in hypercalciuric kidney stones.