Un caso de hipercalcemia hipocalciúrica de causa genética en niño prepúber / Genetic hypercalcemic hypocalciuria in a prepubertal boy

Un paciente de 12 años consultó por vómitos recurrentes asociados con cefaleas, con varios episodios durante 7 meses, y retraso ponderal secundario a esa sintomatología. Había recibido previamente un tratamiento con antibióticos e inhibidores de la bomba de protones, por diagnóstico de gastritis a Helicobacter pylori, después de biopsia gástrica realizada durante una videoendoscopía digestiva alta. Se desconoce su historia familiar porque es hijo adoptivo. Al examen físico el paciente estaba adelgazado, sin tumoración a nivel de cuello; presentaba genitales prepuberales. Como el paciente continuó con vómitos cíclicos recurrentes, siguieron exámenes complementarios donde se constató en 2 oportunidades hipercalcemia (13,2-13,6 mg/dl), acompañada de hipofosfatemia (2,7 mg/dl). Con un diagnóstico presuntivo de hiperparatiroidismo primario se realizaron dosajes de laboratorio: calcemia total e iónica elevada (12,1 y 5,6mg/dl respectivamente), fosfatemia baja (2,8 mg/dl), fosfatasa alcalina sérica normal (151 mU/ml), PTH sérica normal (47,1 pg/ml), 25(OH)vitamina D sérica adecuada (22 ng/ml). La ecografía de glándulas tiroides y paratiroides mostró una imagen redondeada hipoecoica, avascular, de 4 mm axial por 4 mm cefalocaudal, por 3 mm ánteroposterior en topografía paratiroidea derecha, planteándose la posibilidad de hipertrofia paratiroidea versus adenopatía. Se realizó estudio de paratiroides por imágenes: centellograma con 99mTc-MIBI y PET-CT con 18F-colina, pero no se constató captación anormal. Se realizaron nuevos estudios de laboratorio: en orina de 24 horas el calcio era de 19 mg, el cociente calcio/creatinina urinaria 0,03 mg/mg, la reabsorción tubular de fósforo normal (82%) y el cociente de las tasas de depuración de calcio y creatinina muy bajo (0,00046). El CTX sérico era bajo. El diagnóstico clínico fue de hipercalcemia hipocalciúrica; ante la falta de antecedentes familiares, se realizó un estudio de posibles mutaciones puntuales en el gen del receptor de calcio (CaSR), hallándose la presencia en heterocigosis de la mutación p.Arg185Gln (p.R185Q) en la posición 554 (c.554G>A) del exón 4 del gene CaSR. Esto implica el cambio de una arginina por glutamina en el codón 185 de la proteína, y confirma el origen genético de la hipercalcemia hipocalciúrica en nuestro paciente. La edad ósea era de 12 años, y se indicó un tratamiento con testosterona i.m. a bajas dosis para acelerar el desarrollo puberal; luego de 4 aplicaciones mensuales su talla se ha incrementado en 4 cm y su peso en 3 kg. Una aplicación subcutánea de denosumab (60 mg) no controló la hipercalcemia. Continuó por un año con hipoorexia y un episodio de vómitos por semana, pero actualmente tiene buen apetito y excelente tolerancia digestiva. Se le ha prescripto cinacalcet oral (AU)

A 12-year-old patient who consulted for recurrent vomiting associated with headaches, with several episodes for 7 months, and low body weight. The patient had previously received treatment with antibiotics and proton pump inhibitors, due to gastritis with Helicobacter pylori, after gastric biopsy performed during videoendoscopy. His family history is unknown because he is an adopted son. At physical examination the patient was thin, without neck tumor; he had prepubertal genitalia. As he patient continued with recurrent vomiting, he was admitted for further evaluation. Laboratory studies revealed hypercalcemia (13.2-13.6 mg/dl), accompanied by hypophosphatemia (2.7 mg/dl). With a presumptive diagnosis of primary hyperparathyroidism, complementary determinations were performed: total and high total and ionized serum calcium (12.1 and 5.6 mg/dl, respectively), normal serum alkaline phosphatase (151 mU/ml), and PTH (47.1 pg/ml), and normal serum 25(OH) vitamin D (32 ng/ml). The ultrasonography of thyroid and parathyroid glands showed a rounded hypoechoic, avascular image, 4 mm in diameter in the lower right parathyroid topography. A parathyroid imaging studies were performed: scintigraphy with 99mTc-MIBI and PET-CT with 18F-choline, but no abnormal uptake was observed. New laboratory studies were carried out: in 24-hour urine the calcium was 19 mg, the urinary calcium/creatinine ratio was 0.03 mg/mg, the tubular reabsorption of phosphorus was normal (82%) and the ratio of clearances rates of calcium and creatinine very low (0.00046). Serum CTX was low. The clinical diagnosis was hypocalciuric hypercalcemia; in the absence of a family history, a study of possible point mutations in the calcium receptor gene (CaSR) was carried out; there was a heterozygous mutation: p.Arg185Gln (p.R185Q) at position 554 (c.554G)>A) of exon 4 of the CaSR gene. This involves the exchange of an arginine for glutamine at codon 185 of the protein, and confirms the genetic origin of the hypocalciuric hypercalcemia in our patient. Bone age was 12 years, and a treatment with testosterone i.m. at low doses to accelerate pubertal development was started; after 4 monthly applications height has increased by 4 cm and weight by 3 kg. Loss of appetite and a weekly episode of postprandial vomiting continued during one yeas, but now his appetite is normal and vomiting has subsided. A subcutaneous application of denosumab (60 mg) did not control hypercalcemia. He has been prescribed oral cinacalcet (AU)

Hipercalcemia hipocalciúrica familiar: Descripción de un caso / Familial hypocalciuric hypercalcemia: A case report

La presencia de hipercalcemia mantenida obliga a realizar pruebas complementarias para determinar su origen. Es benigna y, generalmente, no requiere tratamiento. La secuenciación del gen CaSR confirma el diagnóstico y evita tratamientos innecesarios. Se presenta a un niño de 12 años, asintomático, con hipercalcemia persistente entre 11,4 y 12,2 mg/dl. El padre y dos hermanos tenían hipercalcemia asintomática. El análisis de laboratorio mostró valores de magnesio, fósforo y vitamina D normales y de hormona paratiroidea llamativamente normal para el valor de la hipercalcemia. Indice de calcio/creatinina urinario: 0,11 mg/mg; y calciuria de 24 h: 1,8 mg/kg/día. Ecografía abdominal, paratiroides, radiografías de huesos largos y densitometría ósea, normales. El estudio genético mostró mutación en exón 6 (c.1651A>G) del gen CaSR (en heterocigosis), confirmada en el padre y los hermanos.

The finding of persistent hypercalcemia suggests doing other medical tests to find the cause. Familial hypocalciuric hypercalcemia is usually benign and it requires no treatment. It is important to do CASR gene sequencing to avoid unnecessary treatments. We report a 12-year-old child, asymptomatic, with calcemia between 11.4 and 12.2 mg/dl. His father and two brothers presented asymptomatic hypercalcemia. The blood test with magnesium, phosphorus, 25(OH)Vit D was normal, remarkable normal parathyroid hormone for the level of hypercalcemia. Urinary calcium/creatinine ratio was 0,11 mg/dl and 24-hour urinary calcium was 1,8 mg/kg per day. Abdominal and parathyroid ecography, long bone radiographs and densitometry were normal. Genetic study showed a mutation, c.1651A>G, in exon 6 of the calciumsensing receptor gene, confirmed in father and brothers, too.

Hipercalcemia hipocalciurica familiar en una paciente con mutación del receptor de calcio: forma atípica de presentación y tratamiento con cinacalcet / Familial hypocalciuric hypercalcemia in a patient with calcium-sensing receptor mutation: atypical clinical presentation and treatment with cinacalcet

El hiperparatiroidismo familiar y la hipercalcemia hipocalciúrica familiar (HHF) constituyen un subgrupo heterogéneo de trastornos con herencia mendeliana, que representan en conjunto el 5% de las causas de hipercalcemia PTH dependiente. La HHF se asocia con mutaciones del gen del receptor sensor de calcio (CaSR). Esta entidad se manifiesta, en la mayoría de los casos, con la presentación asintomática y familiar de hipercalcemia e hipocalciuria y valores elevados o normales de hormona paratiroidea (PTH). Los avances en la biología molecular han contribuido al diagnóstico, evaluación del fenotipo de cada entidad y elección del tratamiento. Se describe el caso de una paciente con hipercalcemia estudiada a partir de una tumoración de cuello asociada con una glándula paratiroides quística. Luego de un exhaustivo proceso diagnóstico se halló en el estudio genético una mutación inactivante en el gen CaSR. Teniendo en cuenta la presencia de la relación clearance calcio/clearance creatinina <0,01 y la falta de respuesta al tratamiento quirúrgico, se consideró la entidad de HHF con forma de presentación atípica. La paciente, sin tratamiento, presentaba un progresivo incremento de la calcemia luego de la cirugía de las glándulas paratiroides, que no se controló con el uso de bifosfonatos y evolucionó con episodios de mareos y desmayos frecuentes sin causa neurológica o cardiovascular detectada. Por lo tanto, se inició el tratamiento con cinacalcet, con el cual se obtuvo una buena respuesta terapéutica: descenso de la calcemia y mejoría de la sintomatología luego de un año de su comienzo. El cinacalcet es una herramienta terapéutica de importancia en estos raros casos de HHF. (AU)

Familial hyperparathyroidism including familial hypocalciuric hypercalcemia (FHH) is an heterogeneous subgroup of disorders with Mendelian inheritance, that account for 5% of PTH dependent hypercalcemia. FHH is associated with mutations of the calcium receptor (CaSR) gene. This entity is manifested by hypercalcemia with hypocalciuria and high or normal levels of parathyroid hormone (PTH) generally asymptomatic and with familial presentation. Advances in molecular biology have contributed to the diagnosis, evaluation of the phenotype of each entity and the choice of treatment. We describe a patient with hypercalcemia diagnosed following the finding of a neck tumor associated with cystic parathyroids. After an exhaustive diagnostic process, an inactivating mutation in the CaSR gene was found. Considering the presence of a ratio clearance calcium / clearance creatinine <0.01 and the lack of response to surgical treatment, HHF entity with atypical presentation was considered. The patient exhibited progressive increase in serum calcium following parathyroid surgery, which was not controlled with the use of bisphosphonates and evolved into episodes of frequent dizziness and fainting, without neurological or cardiovascular causes. Treatment with cinacalcet was initiated, with a good therapeutic response. The use of cinacalcet is a useful therapeutic tool in these rare cases of FHH. (AU)

New mutation in the CASR gene in a family with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) / Nova mutação no gene CASR em uma família com hipercalcemia hipocalciúrica familiar (HHF) e hiperparatireoidismo neonatal grave (HPTNG)

A loss of calcium-sensing receptor (CASR) function due to inactivating mutations can cause familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism (NSHPT). NSHPT represents the most severe expression of FHH and courses as a life-threatening condition. The aim of this study was to identify and characterize a CASR mutation in a female infant brought to the health service due to dehydration, apathy, lack of breast feeding and severe hypercalcemia. Molecular analysis was performed on genomic DNA of the index case and her parents. A novel homozygous mutation (p.E519X) in CASR was identified in the proband; both mother and father had the same mutation in heterozygous state, confirming their FHH condition. The mutation results in a truncated and inactive protein due to the lack of transmembrane and intracellular domains. The identification of this novel CASR gene mutation established the basis of hypercalcemia in this family and allowed a genetic counseling.

Mutações inativadoras no gene do sensor do cálcio (CASR) podem causar hipercalcemia hipocalciúrica familiar (HHF) ou hiperparatireoidismo neonatal grave (HPTNSG). A HPTNS representa a forma mais grave da HHF cursando com risco de vida. O objetivo deste estudo foi identificar e caracterizar uma mutação no gene CASR de uma criança do sexo feminino levada ao hospital em decorrência de desidratação, apatia, dificuldade para mamar e hipercalcemia grave. A análise molecular foi realizada a partir do DNA genômico do caso índice e de seus pais. Uma nova mutação em homozigose (p.E519X) foi identificada no caso índice; ambos, mãe e pai, apresentaram a mesma mutação em heterozigose, o que os caracteriza como portadores de HHF. Essa alteração resulta em uma proteína truncada e inativa devido à falta dos domínios transmembrana e intracelular. A identificação dessa nova mutação estabeleceu a causa da hipercalcemia na família e permitiu o aconselhamento genético.

Hiperparatireoidismo primário familiar isolado: análise e descrição de uma família com seis casos índices: [carta ao editor] / Familial isolated primary hyperparathyroidism: description and analyses of six cases: [letter to the editor]

Objetivamos descrever e analisar uma família com seis casos de hiperparatireoidismo familiar isolado (HFI), uma rara doença hereditária de padrão autossômico dominante, caracterizada por hiperparatireoidismo primário sem associação com outras doenças ou tumores endocrinológicos. O diagnóstico foi realizado através da demonstração de hipercalcemia, aumento dos níveis de paratormônio e tumores de paratireóide à histopatologia, excluindo-se neoplasias endócrinas múltiplas do tipo 1 (NEM 1) e do tipo 2a (NEM 2a), além da síndrome hiperparatireoidismo/tumor de mandíbula (HPT/TM). Analisamos a descrição dos exames diagnósticos iniciais, a abordagem cirúrgica, os laudos histopatológicos pós-operatórios e suas evoluções. A primeira paciente operada neste instituto há 20 anos, recidivou onze anos após, e possuía uma irmã com diagnóstico prévio, o que motivou a investigação de outros familiares. A observação do caráter familial nesses pacientes contribuiu para a facilitação diagnóstica e encaminhamento terapêutico dos mesmos, assim como a orientação clínica e genética à família.

Our objective is to evaluate and describe one family with six cases of familial isolated primary hyperparathyroidism (HFI), a rare hereditable disorder with an autossomal dominant mode of inheritance. It is characterized by a primary hyperparathyroidism without association with other endocrine tumors or diseases. The HFI diagnosis relied on the demonstration of hypercalcemia, inappropriately high levels of parathyroid hormone, and parathyroid adenomas, plus exclusion of NEM 1/2a and HPT/TM syndrome in this family. We analyzed the description of the first diagnosis, surgical approach, postoperative histopathological results and their development process. The first patient, treated in our institute twenty years ago, has recidivated eleven years after the treatment. Her sister had had the same diagnosis, which motivated us to investigate theirs relatives. The analysis of the characteristics that run in these patients' family has contributed to facilitate their diagnosis and therapeutic treatment, including clinical and genetic orientation of this family.

The calcium-sensing receptor and related diseases / O receptor sensor de cálcio e doenças associadas

The calcium-sensing receptor (CASR) adjusts the extracellular calcium set point regulating PTH secretion and renal calcium excretion. The receptor is expressed in several tissues and is also involved in other cellular functions such as proliferation, differentiation and other hormonal secretion. High extracellular calcium levels activate the receptor resulting in modulation of several signaling pathways depending on the target tissues. Mutations in the CASR gene can result in gain or loss of receptor function. Gain of function mutations are associated to Autossomal dominant hypocalcemia and Bartter syndrome type V, while loss of function mutations are associated to Familial hypocalciuric hypercalcemia and Neonatal severe hyperparathyroidism. More than one hundred mutations were described in this gene. In addition to calcium, the receptor also interacts with several ions and polyamines. The CASR is a potential therapeutic target to treatment of diseases including hyperparathyroidism and osteoporosis, since its interaction with pharmacological compounds results in modulation of PTH secretion.

O receptor sensor de cálcio (CASR) ajusta o set point do cálcio extracelular através da regulação da secreção de PTH e da excreção renal de cálcio. O receptor é expresso em diversos tecidos e também está envolvido em outras funções celulares como proliferação, diferenciação e secreção de outros hormônios. Concentrações altas de cálcio extracelular ativam o receptor resultando em modulação de inúmeras vias de sinais intracelulares dependendo do tecido-alvo. Mutações no gene do CASR podem resultar em ganho ou perda de função do receptor. Mutações com ganho de função são associadas à Hipocalcemia autossômica dominante e à Síndrome de Bartter tipo V, enquanto que mutações com perda de função são associadas à Hipercalcemia hipocalciúrica familiar e ao Hiperparatireoidismo neonatal grave. Mais de cem mutações foram descritas neste gene. Além do cálcio, o receptor também interage com inúmeros íons e poliaminas. CASR é um alvo terapêutico potencial para tratamento de doenças incluindo hiperparatireoidismo e osteoporose, pois a sua interação com compostos farmacológicos resulta em modulação da secreção de PTH.

A Case Report of Familial Benign Hypocalciuric Hypercalcemia: A Mutation in the Calcium-Sensing Receptor Gene

Familial benign hypocalciuric hypercalcemia (FBHH) is an autosomal dominant trait with high penetrance, clinically manifestating a relatively benign, lifelong, persistent hypercalcemia and hypocalciuria without hypercalcemic related complications. The calcium-sensing receptor (CaSR) plays an important role in the regulation of PTH secretion and calcium metabolism. Here we present a family with FBHH of an autosomal dominant inheritance. A heterozygous mutation of E297K (GAG -> AAG, exon 4) of CaSR gene was found in 3 family members. To our knowledge, it is the first confirmed case of FBHH with CaSR gene mutation in Korea.

Hipercalcemia hipocalciurica debida a una mutacion de novo del gen del receptor sensor del calcio / Hypocalciuric hypercalcemia due to de novo mutation of the calcium sensing receptor

El objetivo de este trabajo es presentar el inusual caso clínico de una paciente de 34 años que consultó para establecer diagnóstico de certeza y conducta terapéutica ante una hipercalcemia asintomática, detectada en un examen dioquímico de rutina. La elevación de la calcemia en ausencia de inhibición de la secreción de parathormona y coincidente con una relación clearance de calcio/clearance de creatina inferior de 0.01, hicieron sospechar el diagnóstico de hipercalcemia hipocalciúrica familiar. La falta de antecedentes familiares llevó a realizar un estudio molecular de la paciente y su grupo familiar. Los resultados de los estudios nos permitieron concluir que la paciente es portadora de una mutación de novo (inactivante) del gen del receptor sensor del calcio. Se incluyen los datos de estudio molecular y una breve revisión bibliográfica del tema.

Extracellular calcium-sensing receptor: structural and functional features and association with diseases

The recently cloned extracellular calcium-sensing receptor (CaR) is a G protein-coupled receptor that plays an essential role in the regulation of extracellular calcium homeostasis. This receptor is expressed in all tissues related to this control (parathyroid glands, thyroid C-cells, kidneys, intestine and bones) and also in tissues with apparently no role in the maintenance of extracellular calcium levels, such as brain, skin and pancreas. The CaR amino acid sequence is compatible with three major domains: a long and hydrophilic aminoterminal extracellular domain, where most of the activating and inactivating mutations described to date are located and where the dimerization process occurs, and the agonist-binding site is located, a hydrophobic transmembrane domain involved in the signal transduction mechanism from the extracellular domain to its respective G protein, and a carboxyterminal intracellular tail, with a well-established role for cell surface CaR expression and for signal transduction. CaR cloning was immediately followed by the association of genetic human diseases with inactivating and activating CaR mutations: familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism are caused by CaR-inactivating mutations, whereas autosomal dominant hypoparathyroidism is secondary to CaR-activating mutations. Finally, we will comment on the development of drugs that modulate CaR function by either activating (calcimimetic drugs) or antagonizing it (calcilytic drugs), and on their potential therapeutic implications, such as medical control of specific cases of primary and uremic hyperparathyroidism with calcimimetic drugs and a potential treatment for osteoporosis with a calcilytic drug

Hiperparatiroidismo primario neonatal severo: presentación de un caso y revisión de la literatura / Neonatal severe primary hyperparathyroidism: report of a case and review of the literature

Se presenta el caso de un neonato en quien se diagnostica hiperparatiroidismo primario neonatal severo, basados en la presencia de hipercalcemia severa con hipofosfatemia concomitante y valores elevados de parathormona. Se hace una revisión de la literatura mundial y nacional sobre el tema y se analiza el diagnóstico diferencial de esta rara entidad