Congenital Hyperphosphatemic Conditions Caused by the Deficient Activity of FGF23.

Congenital diseases that could result in hyperphosphatemia at an early age include hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) and congenital hypoparathyroidism/pseudohypoparathyroidism due to the insufficient activity of fibroblast growth factor (FGF) 23 and parathyroid hormone. HFTC/HHS is a rare autosomal recessive disease caused by inactivating mutations in the FGF23, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) genes, resulting in the excessive cleavage of active intact FGF23 (FGF23, GALNT3) or increased resistance to the action of FGF23 (KL). Massive ectopic calcification, known as tumoral calcinosis (TC), is seen in periarticular soft tissues, typically in the hip, elbow, and shoulder in HFTC/HHS, reducing the range of motion. However, other regions, such as the eye, intestine, vasculature, and testis, are also targets of ectopic calcification. The other symptoms of HFTC/HHS are painful hyperostosis of the lower legs, dental abnormalities, and systemic inflammation. Low phosphate diets, phosphate binders, and phosphaturic reagents such as acetazolamide are the treatment options for HFTC/HHS and have various consequences, which warrant the development of novel therapeutics involving recombinant FGF23.

Role of Matrix Gla protein in midface development: Recent advances.

Craniofacial development is a delicate process that involves complex interactions among cells of multiple developmental origins, their migration, proliferation, and differentiation. Tissue morphogenesis of the craniofacial skeleton depends on genetic and environmental factors, and on specific signaling pathways, which are still not well understood. Developmental defects of the midface caused by the absence, delays, or premature fusion of nasal and maxillary prominences vary in severity; leading to clefts, hypoplasias, and midline expansion. In the current review, we focus on the importance of the chondrocranium in craniofacial growth and how its impaired development leads to midface hypoplasia. More importantly, we reported how Matrix Gla protein (MGP), a potent inhibitor of extracellular matrix mineralization, facilitates midface development by preventing ectopic calcification of the nasal septum. In fact, MGP may act as a common link in multiple developmental pathologies all showing midface hypoplasia caused by abnormal cartilage calcification. This brief review discusses the gap in knowledge in the field, raises pertinent questions, which remain unanswered, and sheds light on the future research directions.

Tumorous congenital calcinosis cutis associated with early childhood epileptic encephalopathy with a pathogenic FGF12 gene variant.

Background: Calcinosis cutis is the deposit of insoluble calcium salts in the skin. It is classified according to its pathogenesis in dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Idiopathic calcinosis is asymptomatic, occurs in healthy patients, and includes scrotal calcinosis, Winer's nodular calcinosis or subepidermal calcified nodules, and familial tumor calcinosis. The latter is a rare condition characterized by periarticular calcium deposition in normocalcemic patients with no bone connection. Case report: The case of a 5-month-old male patient, who on the seventh day of life was hospitalized for multifactorial jaundice, late neonatal sepsis, and apnea with epileptic seizures is described. His evolution was torpid, with hospital admissions due to epileptic seizures that were difficult to manage with partial response to the use of diphenylhydantoin and electrolyte alterations. By means of exome sequencing directed, a pathogenic variant of wrong direction in FGF12 was detected and the diagnosis of early epileptic encephalopathy number 47 was confirmed. Also, the patient showed disseminated congenital dermatosis to lower extremities affecting thighs, asymptomatic, bilateral and symmetrical, constituted by hypopigmentation and fovea hard to deep palpation. The biopsy showed dystrophic calcification. Conclusions: The case of an infant with deep congenital cutis calcinosis associated with a pathogenic variant in the FGF12 gene with epileptic encephalopathy is described. To date, this clinical situation has not been previously reported in the literature.

Background: Introducción">La calcinosis cutis es el depósito de sales insolubles de calcio en la piel y se clasifica, de acuerdo con su patogénesis, en distrófica, metastásica, idiopática, iatrogénica y calcifilaxis. La calcinosis idiopática se presenta en pacientes sanos y es asintomática; incluye la calcinosis escrotal, la calcinosis nodular de Winer o nódulos calcificados subepidérmicos y la calcinosis tumoral familiar. Esta última es una condición rara que se caracteriza por el depósito de calcio periarticular en pacientes normocalcémicos sin conexión al hueso. Caso clínico: Paciente de sexo masculino de 5 meses de edad, quien al séptimo día de vida fue hospitalizado por ictericia multifactorial, sepsis neonatal tardía y apnea con crisis epilépticas. La evolución fue tórpida, con ingresos hospitalarios por crisis epilépticas de difícil manejo, respuesta parcial a la difenilhidantoína y descontrol electrolítico. Mediante la secuenciación del exoma dirigido se detectó una variante patogénica de sentido equivocado en FGF12 que confirmó el diagnóstico de encefalopatía epiléptica temprana número 47. Además, el paciente presentó dermatosis congénita diseminada a las extremidades inferiores con afección en muslos, asintomática, bilateral y simétrica, constituida por hipopigmentación y fóveas duras a la palpación profunda. La biopsia mostró calcificación distrófica. Conclusiones: Se presenta el caso de un lactante con calcinosis cutis congénita profunda asociada con una variante patogénica en el gen FGF12 y con encefalopatía epiléptica, situación clínica que, a la fecha, no había sido reportada en la literatura.

Cardiac Calcified Amorphous Tumor in a Newborn.

Calcified amorphous tumors (CATs) of the heart are rare, nonneoplastic, intracavitary lesions, previously thought of as pseudotumors, hamartomas, or calcified thrombi, only reported in few adults in the available literature. This report describes a case of a pedunculated oscillating CAT arising from the left atrial appendage that prolapses through the mitral valve and causes severe mitral regurgitation in a newborn. This is the only case of cardiac CAT described in a neonate.

Sturge-Weber syndrome accompanied with multiple congenital intracranial lesions.

Sturge-Weber syndrome is one of the neurocutaneous syndromes. It is a rare, nonfamiliar disease that is characterized by facial port-wine stain, leptomeningeal angiomatosis, choroidal angioma, buphthalmos, intracranial calcification, cerebral atrophy, mental retardation, glaucoma, seizures and hemiparesis. CT and MR are complementary in the evaluation of this disease. Epilepsy is an essential feature of Sturge-Weber syndrome and it has a major significance for prognosis and treatment. We report a 2-year-old boy with Sturge-Weber syndrome who had in addition an intracranial lipoma, a temporal arachnoid cyst and a porencephalic cyst. This combination of intracranial lesions with Sturge-Weber syndrome has not been previously reported.

Life-threatening subdural hematoma after aortic valve replacement in a patient with Heyde syndrome: a case report.

BACKGROUND: Heyde syndrome is known as a triad of calcific aortic stenosis, anemia due to gastrointestinal bleeding from angiodysplasia, and acquired type 2A von Willebrand disease. This acquired hemorrhagic disorder is characterized by the loss of the large von Willebrand factor multimers due to the shear stress across the diseased aortic valve. The most frequently observed type of bleeding in these patients is mucosal or skin bleeding, such as epistaxis, followed by gastrointestinal bleeding. On the other hand, intracranial hemorrhage complicating Heyde syndrome is extremely rare. CASE PRESENTATION: A 77-year-old woman presented to our hospital with severe aortic stenosis and severe anemia due to gastrointestinal bleeding and was diagnosed with Heyde syndrome. Although aortic valve replacement was performed without recurrent gastrointestinal bleeding, postoperative life-threatening acute subdural hematoma occurred with a marked midline shift. Despite prompt surgical evacuation of the hematoma, she did not recover consciousness and she died 1 month after the operation. CONCLUSIONS: Postoperative subdural hematoma is rare, but it should be kept in mind as a devastating hemorrhagic complication, especially in patients with Heyde syndrome.

Congenital bilateral calcinosis cutis of the hands.

Calcinosis cutis is the cutaneous deposition of calcium phosphate. We present the first reported case of symmetrical calcium deposits being present in both hands at birth.

[Congenital varicella: limits of prenatal diagnosis]. / La varicelle congénitale: les limites du diagnostic prénatal.

INTRODUCTION: Primary varicella infection during pregnancy is uncommon. Fetal varicella syndrome is unusual when varicella occurs after 20 weeks of gestation. CASE REPORT: A mother contracted chicken pox at 21 weeks and 3 days of gestation. Monthly monitoring was assured by the center for prenatal diagnosis, starting from 23 weeks. At 36 weeks, foetal echography detected liver calcifications, without other lesions. At 38 weeks, the patient went into spontaneous labour and delivered a male baby. The baby presented cicatricial skin lesions all over the body and scalp. The cerebral scan detected calcifications and a bilateral chorioretinitis was noticed. At 12 months, the infant had delayed psychomotor acquisitions, a cerebral cortical atrophy and blindness. CONCLUSION: The presence of fetal liver calcifications after chicken pox in the mother is a seldom reported sign. In our observation, liver calcifications were the single sign of a severe fetal damage.

Calcinosis cutis congénita tumoral asociada con encefalopatía epiléptica infantil temprana con variante patogénica en el gen FGF12 / Tumorous congenital calcinosis cutis associated with early childhood epileptic encephalopathy with a pathogenic FGF12 gene variant

Resumen Introducción: La calcinosis cutis es el depósito de sales insolubles de calcio en la piel y se clasifica, de acuerdo con su patogénesis, en distrófica, metastásica, idiopática, iatrogénica y calcifilaxis. La calcinosis idiopática se presenta en pacientes sanos y es asintomática; incluye la calcinosis escrotal, la calcinosis nodular de Winer o nódulos calcificados subepidérmicos y la calcinosis tumoral familiar. Esta última es una condición rara que se caracteriza por el depósito de calcio periarticular en pacientes normocalcémicos sin conexión al hueso. Caso clínico: Paciente de sexo masculino de 5 meses de edad, quien al séptimo día de vida fue hospitalizado por ictericia multifactorial, sepsis neonatal tardía y apnea con crisis epilépticas. La evolución fue tórpida, con ingresos hospitalarios por crisis epilépticas de difícil manejo, respuesta parcial a la difenilhidantoína y descontrol electrolítico. Mediante la secuenciación del exoma dirigido se detectó una variante patogénica de sentido equivocado en FGF12 que confirmó el diagnóstico de encefalopatía epiléptica temprana número 47. Además, el paciente presentó dermatosis congénita diseminada a las extremidades inferiores con afección en muslos, asintomática, bilateral y simétrica, constituida por hipopigmentación y fóveas duras a la palpación profunda. La biopsia mostró calcificación distrófica. Conclusiones: Se presenta el caso de un lactante con calcinosis cutis congénita profunda asociada con una variante patogénica en el gen FGF12 y con encefalopatía epiléptica, situación clínica que, a la fecha, no había sido reportada en la literatura.

Abstract Background: Calcinosis cutis is the deposit of insoluble calcium salts in the skin. It is classified according to its pathogenesis in dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Idiopathic calcinosis is asymptomatic, occurs in healthy patients, and includes scrotal calcinosis, Winer's nodular calcinosis or subepidermal calcified nodules, and familial tumor calcinosis. The latter is a rare condition characterized by periarticular calcium deposition in normocalcemic patients with no bone connection. Case report: The case of a 5-month-old male patient, who on the seventh day of life was hospitalized for multifactorial jaundice, late neonatal sepsis, and apnea with epileptic seizures is described. His evolution was torpid, with hospital admissions due to epileptic seizures that were difficult to manage with partial response to the use of diphenylhydantoin and electrolyte alterations. By means of exome sequencing directed, a pathogenic variant of wrong direction in FGF12 was detected and the diagnosis of early epileptic encephalopathy number 47 was confirmed. Also, the patient showed disseminated congenital dermatosis to lower extremities affecting thighs, asymptomatic, bilateral and symmetrical, constituted by hypopigmentation and fovea hard to deep palpation. The biopsy showed dystrophic calcification Conclusions: The case of an infant with deep congenital cutis calcinosis associated with a pathogenic variant in the FGF12 gene with epileptic encephalopathy is described. To date, this clinical situation has not been previously reported in the literature.

An unusual malformation of the forebrain and concomitant destructive encephalopathy with calcifications.

A 9-year old boy with profound mental retardation and severe neurologic deficit presented an unusual malformation of the forebrain distinguished by the following features: 1) microtelencephalon, alobulation, afissuration, and abnormal convolutional pattern; 2) persistence of hippocampal formation at its embryonic site in the dorsomedial wall of the telencephalon; 3) hypoplasia and abnormal configuration of ventricles; 4) agenesis of cerebral commissures; and 5) abnormal location and orientation of gray structures. Important concomitant findings characterized by severe destructive lesions, massive calcification, granular ependymitis, and low grade inflammation were suggestive of late sequelae of an infectious process, possibly congenital. Transplacental transmission of an unidentified pathogen with teratogenic properties was hypothesized as the probable cause. The teratogenic insult started in an early embryonic period and affected primarily the development of the neopallium in the telencephalic wall. The arrested development of the neopallium disrupted the chain of interdependent developmental events; consequently characteristic morphological modifications normally induced by the continuous growth and differentiation of the neopallium failed to occur or took an abnormal course. The name architelencephalon (Greek: arche, beginning; telencephalon, cerebral hemispheres) proposed for this particular malformation of the forebrain indicates its resemblance both to the human brain at early stages of development and also to mammalian brains on a lower level of phylogeny. Associated anomalies included an unilateral microphthalmia with cataract, severe stenosis of the aqueduct of Sylvius and macrocephaly. The microphthalmia was either a developmental anomaly or was infectious in origin. The stenosis of the aqueduct was attributed to granular ependymitis. Tearing of the thin dorsal diencephalic plate and arachnoid membrane and escape of the cerebrospinal fluid into the subdural space probably accounted for the macrocephaly.

Congenital PCB poisoning: a reevaluation.

A review of the literature reveals a need to clarify the pathologic physiology of congenital polychlorinated biphenyl (PCB) poisoning, which is characterized by intrauterine growth retardation, brown staining of the skin and mucous membranes, as in Addison's disease, natal teeth, widely open fontanelles and sagittal suture and apparent overgrowth of the gingiva. The skull abnormalities may represent irregular calcification, with natal teeth appearing because the bone of the mandible is penetrated more easily than usual. Some fetuses were poisoned at the time the mothers ingested the oil; others were affected in the subsequent years from residual contamination in the mothers' bodies. The misadventure in Japan was repeated in Taiwan in 1979. The seven congenital cases in Taiwan reported thus far seem to differ from those in Japan. In Taiwan the noses were somewhat black, two of the infants did not have low birth weight and the osseous abnormalities of the skull and gingival hyperplasia were not observed. Systematic followup studies should be made in Taiwan of the children born within 2 years of maternal poisoning with PCBs. Special attention should be given to age at first dentition and skull X-rays for spotty calcification, among other measures of physical, neurologic and intellectual development.

Discordant infantile encephalopathy with symmetrical thalamic calcifications in identical twins.

Connatal thalamic calcifications in apparently uneventful pregnancies have been described in various case reports and in a single report in two sibs. On the other hand, this lesion is known to occur after a hypoxic-ischemic accident in the immature brain. In the present report infantile encephalopathy with symmetrical thalamic calcifications is observed in one sib of a monozygous twin pair. This observation adds to the evidence that the condition is acquired, most probably on the basis of hypoxia-ischemia, and provides strong evidence against autosomal-recessive inheritance.

Agenesis of corpus callosum and intraventricular lipomas.

Intracranial lipomas are rare and usually do not have clinical expression. They are located most commonly in the interhemispheric fissure and may also be found in the quadrigeminal, ambient, chiasmatic, interpeduncular, sylvian, and perimesencephalic cisterns. Interhemispheric lipomas may be associated with choroid plexus lipomas. The ultrasonography, computed tomography, and magnetic resonance imaging findings are reported in a neonate with lateral ventricular choroid plexus lipomas and interhemispheric lipoma associated with agenesis of the corpus callosum.

Neuroradiographic abnormalities in congenital cytomegalovirus infection.

To determine the spectrum of neuroradiographic abnormalities associated with congenital cytomegalovirus (CMV) infection, CT brain scans of 15 infants with symptomatic infection were reviewed. The initial CT scans were abnormal in 13 patients. Abnormalities included intracranial calcifications, cortical atrophy, ventricular enlargement, subdural effusions, porencephaly and polycystic encephalomalacia. Intracranial calcifications were present in 33% of the infants. In addition, three of the 15 infants developed progressive hydrocephalus which required ventriculoperitoneal shunt placement. These cases illustrate that congenital CMV infection causes a variety of structural CNS lesions and suggest that progressive hydrocephalus may be a relatively common consequence of symptomatic congenital CMV infection.

A lethal association of congenital apnea with brainstem tegmental necrosis.

We present a female with premature birth, polyhydramnios, congenital apnea, cranial nerve palsies, orofacial and limb anomalies. Neuroimaging revealed calcifications along the vental margin of the caudal fourth ventricle. Neuropathologic findings at postmortem examination were consistent with brainstem tegmental necrosis and olivary hypoplasia, a rare lethal entity that should be considered in the differential diagnosis of congenital apnea.

Idiopathic arterial calcification of infancy in newborn siblings with unusual light and electron microscopic manifestations.

We report two cases of idiopathic arterial calcification of infancy (IACI) occurring in newborn siblings. Unusual gross and light microscopic findings included calcification of multiple nonarterial tissues, renal infarction, and macroscopic aortic involvement. One case manifested an extensive acute panarteritis suggesting that IACI may be the result of an inflammatory or infectious process. Ultrastructural examination confirmed that the mineral deposits were hydroxyapatite and also indicated that they contained iron. Calcified tissue components included smooth-muscle cells, fibroblasts, and collagen fibers, as well as elastic fibers. No matrix vesicles or mitochondrial calcifications that may serve as nucleation sites for crystalline calcium phosphate were identified. Thus, the mechanism of calcification in IACI may be unique, and may relate to altered iron metabolism.

Complete heart block in the 18p--syndrome. Congenital calcification of the atrioventricular node.

Complete heart block exists when the atria and ventricles beat completely independently of each other. It is heterogeneous with respect to pathogenesis. Occasionally, complete heart block may be symptomatic in infancy. Rarely, it is associated with genetic syndromes. Cardiac abnormalities are unusual in the 18p-syndrome. We describe a female stillborn infant who had 18p-syndrome with hydrops fetalis and complete heart block secondary to atrioventricular node calcification.