Further delineation of phenotype and genotype of Kenny-Caffey syndrome type 2 (phenotype and genotype of KCS type 2).

BACKGROUND: Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in FAM111A gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention. METHODS: We present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father-to-daughter transmission, adding to the limited literature. Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases. RESULTS: There were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G>A (p.Arg569His) variant, and one child harbouring a c.1531T>C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases. CONCLUSION: We provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father-to-daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention.

Rare cause of recurrent hypocalcaemia and functional hypoparathyroidism due to hypomagnesaemia caused by TRPM6 gene mutation.

Magnesium is essential for the functioning and release of parathyroid hormone. Therefore, its deficiency can present as functional hypoparathyroidism. This case report describes a rare inherited disorder called congenital hypomagnesaemia with secondary hypocalcaemia due to TRPM6 gene mutation. This disease clinically and biochemically mimics hypoparathyroidism. However, unlike hypoparathyroidism, it can be treated only by long-term oral magnesium supplements. The patient presented to us with recurrent hypocalcaemic convulsions. The laboratory picture in each admission was similar to that of hypoparathyroidism. However, the hypocalcaemia persisted, and it was noticed to be associated with persistent hypomagnesaemia. A defect in the tubular magnesium reabsorption was postulated and a genetic analysis of the patient was done, which revealed a TRPM6 mutation causing hypomagnesaemia by excessive renal excretion of magnesium. The child responded well to oral magnesium supplements and is currently developmentally appropriate for her age and thriving well.

Late diagnosis of DiGeorge syndrome in a 13-year-old male with subclinical course of the disease - case report and literature review.

DiGeorge syndrome is associated with microdeletion of chromosome 22q11. Hypoplasia of the thymus, hypoparathyroidism, facial malformations and cardiac defects as well as learning difficulties are typical features of the disease. On the other hand hypocalcemia related to hypoparathyroidism is not present in every patient and can develop later and be persistent or transient and is often masked by the other signs or symptoms. We described a 13-year-old boy diagnosed with DiGeorge syndrome, after a few years of nonspecific signs and symptoms, and a microarray examination performed because myopathy was suspected on the basis of elevated creatine kinase activity. Only after molecular confirmation of DiGeorge syndrome the patient was referred to a pediatric endocrinologist and proper therapy started. Looking back to his medical history, low calcium levels were at least 2 times reported in the medical records, the child had learning difficulties, speech disturbances, and submucosal cleft palate suspicion. In conclusion it is important to educate general practitioners and pediatricians to check the serum calcium levels in patients presenting with nonspecific, muscular signs and symptoms.

HDR syndrome in a Colombian woman with a genital tract malformation: first case report in Latin America / Síndrome HDR en una mujer colombiana con una malformación genitourinaria: primer reporte de caso en Latinoamérica

ABSTRACT Objectives Hypoparathyroidism, sensorineural deafness and renal disease (HDR) syndrome, also known as Barakat syndrome, is an autosomal dominant transmission hereditary disease with a wide range of penetrance and expressivity. Haploinsufficiency of the GATA3 two finger zinc transcription factor is believed to be its cause. This is the first time this orphan disease is reported in Latin America, so the publishing of this report is expected to raise awareness on these types of syndrome, that are usually underdiagnosed in our region, which in turn causes an increase in the years lost to disability (YLDs) rates, as well as higher costs to be assumed by public health systems. Methods A 36-year-old Colombian woman diagnosed with parathyroid gland agenesis was referred from the Endocrinology Service to the Outpatient Service. According to her medical record, in the past she had developed hypocalcaemia, left renal agenesis, hypoparathyroidism, bicornate uterus and sensorineural hearing loss. Through a genetic analysis a pathological mutation on the short arm of the GATA 3 gen (c.404dupC, p Ala136 GlyfsTER 167) was confirmed, which led to a HDR syndrome diagnosis. Discussion This case proves that there is a possibility that mutations described in other continents may be developed by individuals from our region. Regardless of ethnicity, Barakat syndrome should be considered as a possible diagnosis in patients presenting the typical triad that has been described for this condition, since there could be underdiagnosis of this disease in Latin-America due to the lack of knowledge on this condition in said region, and that genetic counseling in these patients is of great importance for the implications of the syndrome in future generations.(AU)

RESUMEN Objetivos El síndrome de hipoparatiroidismo, sordera neurosensorial y displasia renal (HDR) también llamado síndrome de Barakat, es una enfermedad hereditaria de transmisión autosómica dominante con amplia penetrancia y expresividad genética. El síndrome es causado por la haploinsuficiencia del factor de transcripción de dedos de Zinc GATA3. Esta es la primera vez que esta enfermedad huérfana es reportada en latinoamerica, y buscamos generar consciencia de la presencia de estas enfermedades, las cuales usualmente son infradiagnósticadas en nuestro medio y llevan a un aumento de años perdidos por discapacidad y costos para el sistema de salud pública. Métodos Una mujer colombiana de 36 años ingresó a consulta externa de genética referida por el servicio de endocrinología por una agenesia de paratiroides. La paciente tenía antecedentes de hipocalcemia, agenesia renal izquierda, hipoparatiroidismo, sordera neurosensorial y útero bicorneo. Se realizó un análisis genético que confirmo una mutación patológica en el brazo corto del gen GATA3 (c.404dupC, p Ala136 GlyfsTER 167) diagnóstica del síndrome de Barakat. Discusión Este caso demuestra la posibilidad de existencia de mutaciones descritas en otros continentes en nuestra población. Sin importar la etnia, el síndrome de Barakat debe ser estudiado en pacientes que presenten la triada típica, ya que podría existir un infra diagnóstico de la enfermedad secundario al desconocimiento de la misma en Latinoamérica y teniendo en cuenta la importancia que tiene la consejería genética en estos pacientes por las implicaciones de la enfermedad en futuras generaciones.(AU)

Hipoparatiroidismo por mutación en el gen del sensor—receptor del calcio (CASR). Aportación de dos nuevos casos / Hypoparathyroidism due to mutation in the calcium sensing receptor (CASR) gene. Presentation of two new cases

El hipoparatiroidismo secundario a mutaciones activadoras en el gen que codifica el sensor receptor del calcio, denominado hipocalcemia autosómica dominante, se caracteriza por hipercalciuria relativa. El tratamiento con calcio y vitamina D conlleva un alto riesgo de nefrocalcinosis, por ello es importante estudiar el gen del sensor receptor del calcio en pacientes con hipoparatiroidismo idiopático. Presentamos dos casos clínicos, uno de ellos con una mutación no descrita previamente (AU)

Hypoparathyroidism secondary to activating mutations in the gene encoding the calcium receptor sensor, termed autosomal dominant hypocalcemia, is characterized by relative hypercalciuria. Treatment with calcium and vitamin D carries a high risk of nephrocalcinosis, so it is important to study the gene of the calcium receptor sensor in patients with idiopathic hypoparathyroidism. We present two clinical cases, one of them with a mutation not previously described (AU)

Hipocalcemia autosómica dominante: una nueva mutación / Autosomal dominant hypocalcaemia: a novel mutation

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Síndromes pluriglandulares autoinmunes / Autoinmune polyendocrinopathy

Los síndromes pluriglandulares autoinmunes (SPA) afectan a múltiples glándulas endocrinas y asocian otras enfermedades autoinmunes. El SPA tipo 1 se presenta con hipoparatiroidismo, candidiasis mucocutánea y enfermedad de Addison, se debe a una mutación en el gen AutoImmune Regulator (AIRE). El diagnóstico es clínico además de la secuenciación del gen AIRE. El SPA tipo 2 se presenta con enfermedad de Addison, diabetes mellitus tipo1 o enfermedad tiroidea autoinmune, se han implicado múltiples genes, entre ellos los del complejo mayor de histocompatibilidad tipo 2. El SPA tipo 3 se caracteriza por la presencia de enfermedad tiroidea autoinmune y otra enfermedad autoinmune, excluyendo la enfermedad de Addison y el hipoparatiroidismo, se han implicado cuatro genes que pueden conferir susceptibilidad. El diagnóstico del SPA tipo 2 y tipo 3 es clínico, aunque la determinación de autoanticuerpos puede ser útil para la evaluación del riesgo de presentar la enfermedad y para confirmar la enfermedad autoinmune en algunos casos. (AU)

Pluriglandular autoimmune syndrome (APS) can affect multiple endocrine glands and is associated with other autoimmune diseases. APS type 1 presents with hypoparathyroidism, mucocutaneous candidiasis and Addison's disease. It is caused by AutoImmune Regulator (AIRE) gene mutation. The diagnosis includes clinical manifestations in addition to AIRE gene sequencing. SPA type 2 presents with Addison's disease, type 1 diabetes, or autoimmune thyroid disease. Multiple genes have been implicated, including those of the class II major histocompatibility complex. SPA type 3 is characterized by autoimmune thyroid disease and other autoimmune disease, excluding Addison's disease and hypoparathyroidism, 4 genes have been implicated and confer susceptibility. The diagnosis of APS type 2 and type 3 includes clinical manifestations, nevertheless, the determination of autoantibodies can be useful to predict the risk of disease manifestation and to confirm the autoimmune disease in some cases. (AU)

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.

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