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Center of Expertise for Rare Endocrine Diseases

Center of Expertise for Rare Endocrine Diseases (C.E.R.E.D) – Disorders of Calcium and Phosphate Metabolism


The Center of Expertise for Rare Endocrine Diseases (C.E.R.E.D) – Disorders of Calcium and Phosphate Metabolism is part of the Endocrinology Unit of the 1st Department of  Propedeutic and Internal Medicine of the Medical School of National and Kapodistrian University of Athens, Greece. The Center is located at LAIKO  General Hospital of Athens (G.H.A).

The network facility service of C.E.R.E.D in LAIKO GHA :

  1. Consists of a multidisciplinary team of several subspecialties dealing with patients harbouring rare endocrine diseases including  disorders of calcium and phosphate metabolism.
  2. Delivers leading care for patients with rare disorders of calcium and phosphate metabolism (hypoparathyroidism, genetic variants of hyperparathyroidism, x-linked hypophosphatenic rickets , tumor-induced osteomalacia etc.)
  3. Provides access to optimal and evidence- based care, prevention programs and scientific innovations for every patient.
  4. Follow treatment plans that are in line with international standards of care and display a patient-friendly and patient-centric approach.
  5. Runs at least twice a month a Specialist Multidisciplinary Team (MDT), depending on the number of patients. In these meetings all new or follow-up patients with disease progression, development of side effects, patient’s request or other related reasons are discussed. In cases of severely affected patients particular attention is paid in improving patients’ quality of life. All disciplines involved in C.E.R.E.D follow specific standard operation procedures (SOP) according to ESE guidelines.
  6. Participates in national and international trials on patients with rare endocrine diseases in the area of calcium and phosphate metabolism disorders and has published multiple original research and review papers in international medical journals
  7. Participates in the preparation and development of national guidelines regarding patients with calcium and phosphate disorders

Specialized Outpatient Clinics are held twice per week under the supervision of  personnel with special interest in calcium and phosphate metabolism consisting of three Specialized endocrinologists, (5) Interns in Endocrinology and (1) secretary trained in the management of the center’s administrative requirements, the administrative management of patients and the recording of patient monitoring and response data and (2) academic research scholars.

More than 200 patients with rare disorders of calcium and phosphate metabolism are currently monitored at the center and more than 20 new patients are estimated each year


The specialized personnel consists of:

  • Dr. Eva Kassi, Associate Professor of Biochemistry and Molecular Endocrinology, who is the Lead and Coordinator of the Center
  • Dr. Maria Yavropoulou, Endocrinology Consultant, who is the Deputy of the Center
  • Gregory Kaltsas, Professor of Internal Medicine and Endocrinology who is the Head of the Endocrinology Unit


  • Dr Marina Tsoli, Endocrinologist, Research Academic Scholar
  • Dr. Sofia Vlachou, Endocrinologist, Research Academic Scholar
  • Dr. Argyro Panagiotakou, Endocrinologist, Research associate
  • Narjes N. Ansari, Molecular Biologist, Post Doc Basic Researcher
  • Maria Lekakou, secretarial office

The organization of the Center also includes all relevant medical specialties according to prerequisites from the European Reference Network for Rare Endocrine Diseases of Calcium and Phosphate Metabolism (Endocrinology, Pediatric Endocrinology, Orthopedics, Oncology, Surgery, Nuclear Medicine, Radiology, Pathology, Nephrology, Genetics and Social Worker), as well as secondary specialties such as Cardiology, Cardiovascular Surgery, Dentistry, Psychiatry, Neurology and Nutrition.


LAIKO General Hospital of Athens is part of the National Health System (NHS) that hosts several Departments of the Medical School of the National and Kapodistrian University of Athens. It operates under the supervision of the Ministry of Health lead by a Chief Executive and a Deputy. The operational delivery is organized through Groups of clinical specialties required to adhere to the organisational policies and procedures that include business continuity policies and operational plans.

Τhe hospital provides 24hours on-call duties  every 4 days and daily from 08.00-14.30 thereby providing availability for continuous admission to hospital for patients with endocrine diseases in need for acute or scheduled inpatient care.


1st Department of Propedeutic and Internal Medicine has a capacity of 42 medical beds for in-patient care that have been fully renovated at 2008.

The C.E.R.E.D provides a defined infrastructure including an organizational management structure naming main partners and core partners, secondary partners, supportive care partners, referring and affiliated partners in a given interdisciplinary cooperation and communication structure.

Data of patients are collected in the hospital –based patients’ database in line with the existing National and European Patient Registry guidelines.

All departments that participate in the Center follow standard operating procedures (Standard Operating Procedures-SOPs) according to guidelines by ΕuroCaNET


1st assessment of out-patient care

Patients can make an appointment for the out-patient clinic using:

  • Hospital appointments contact number: 1535
  • Center secretary contact number: 2107462217
  • E-mail: Laiko@gmail.com


Out-patient clinic for Bone Metabolism and Calcium and Phosphate Disorders MONDAY 09.00-1400 16 Sevastoupoleos str.

(LAIKO Specialized Outpatient Clinics)

5th floor, Room Νο. 5

Dr. Eva Kassi
Out-patient clinic for Bone Metabolism and Calcium and Phosphate Disorders WEDNESDAY 09.00-1400 16 Sevastoupoleos str.

(LAIKO Specialized Outpatient Clinics)

5th floor, Room Νο. 5

Dr. Maria Yavropoulou



Diagnostic work-up consists mainly of blood and urine laboratory tests, radiology tests (X-rays, ultrasound, computed tomography, magnetic resonance tomography, bone scintigraphy, sestamibi scintigraphy) and, occasionally, invasive procedures such as bone biopsy.

Further testing that may be required include  reviewing  of pathology samples, functional imaging including 68Gallium-DOTATATE -PET/CT, 18FDG-PET/CT and genetic (molecular) testing.

Functional testing with somatostatin receptors scintigraphy (Octreoscan) is conducted at the Nuclear Medicine Department of LAIKO GHA or at the  Foundation of Medical and Biological Research of the Academy of Athens, when  68Gallium-DOATATE-PET/CT  and  18FDG-PET are required.


Treatment consists of surgical procedures, drug therapy, molecular targeted therapy and/or calcium, phosphate and vitamin D supplements. In selected cases a combination of treatment (such as surgery and drug therapy) may be appropriate.

 Surgical treatment is provided at two General Surgery Departments (1st and 2nd) of LAIKO General Hospital of Athens.


The Centre personnel work in close contact with numerous Departments of LAIKO G.H.A as well as Departments of other hospitals and Private Diagnostic Centers.

 LAIKO General Hospital of Athens

  • 1st Department of General Surgery, (Scientific Supervisor: Assoc. Professor Dimitris Dimitroulis)
  • 2nd Department of General Surgery, (Scientific supervisor: Assoc. Professor Ioannis Karavokyros)
  • 1st Department of Pathology, (Scientific Supervisor: Professor George Agrogiannis)
  • Department of Biochemistry, (Scientific Supervisor: Professor Aggeliki Papapanagiotou)
  • Department of Cardiology, (Scientific Supervisor: Dr. George Anastasiadis)
  • Department of Nephrology, (Scientific Supervisor: Professor Ioannis Mpoletis)
  • Department of Nuclear Medicine, (Scientific Supervisor: Dr. Antigoni Velidaki)
  • Department of Radiology and Invasive Radiology, (Scientific Supervisor: Dr. Konstantinos Revenas)
  • Department of Orhopedics, (Scientific supervisor: Dr. Eva Papakitsou)
  • Department of Gynecology, (Scientific supervisor: Dr. Konstantinos Giannakopoulos)
  • Division of Neurology, (Scientific Supervisor: Dr. Athina Efthymiou)
  • Social Workers Division, (Scientific Supervisor: Kyriaki Katsetou)
  • Division of Clinical Dieticians, (Scientific Supervisor: Dr. Liana Poulia)
  • Division of Physiotherapy, (Scientific Supervisor: Chariklia Lagiou)

Medical School, National and Kapodistrian University of Athens

  • Department of Biology (Scientific Supervisor: Professor Panagoulia Kollia)
  • Department of Biological Chemistry (Scientific Supervisor: Assoc. Professor Eva Kassi)

ATΤIKOΝ General Hospital of Athens

  • Department of Thoracosurgery, (Scientific Supervisor: Professor Periklis Tomos)
  • Department of Nuclear Medicine, (Scientific Supervisor: Prof. Sofia Hatzhioannou)

AIGINITION General Hospital of Athens

  • Department of Psychiatry, (Scientific Supervisor: Ioannis Zervas)

Diagnostic Centers in the Private Sector-Athens

  • Department of CT/MRI, BIOIATRIKI Diagnostic Center, Peristeri, Athens (Scientific supervisor Dr. D. Kolomodi)
  • Clinical Laboratory Genetics- ACCESS TO GENOME-ATG, (Scientific Supervisor: Dr. Emmanouil Manolakos, Dr. Ioannis Papoulidis)

Foundation of Medical-Biological Research of the Academy of Athens

  • Department of PET/CT, (Scientific Supervisor: Prof. Sofia Hatzhioannou)

 AGIA SOFIA Children’s Hospital of Athens

  • Institute of Children’s Health, (Scientific Supervisor: Dr. Artemis Doulgeraki)

Information For Patients

Calcium and Phosphate Homeostasis is of major importance to a large number of physiological processes thereby affecting several organ systems typically bone, muscles, kidney, brain with consequences on the patient’s quality of life and on the risk of chronic disability.

These diseases often manifest with unspecific symptoms (like seizure, failure to thrive) leading to a severe delay in diagnosis. For several of them, treatment options are available (or under development), upon diagnosis. However, it is only recently that long-term consequences and burden of the diseases have been characterized.

Parathyroid hormone (PTH), which is secreted by the parathyroid glands, and Vitamin D, which is mainly produced in the skin from sun exposure and is activated in the kidney, are the main hormones that regulate the calcium homeostasis, while these two hormones along with FGF-23 (a bone-derived hormone) are responsible for the phosphorus homeostasis. Dysregulation of the secretion of these hormones leads to hypocalcemia, hypercalcemia and disorders of phosphate balance.

The PTH-dependent hypercalcemia diseases cover a wide range of sporadic cases of primary hyperparatahyroidism as well as genetic syndromes predisposing to hyperparathyroidism, and in some complex cases simple parathyroidectomy may not be completely curative. Hypocalcemia, on the other hand covers hypoparathyroidism, autosomal dominant hypocalcemia as well as vitamin D dependent rickets (VDDR). Disorders of phosphate imbalance share abnormal bone and teeth structure, as well as a dysregulation of the FGF23 endocrine system.

Patients suffering from the following diseases can turn to C.E.R.E.D for specialist care.

Primary Hyperparathyroidism

Hyperparathyroidism is caused by excessive secretion of PTH by one or more parathyroid glands. It leads to hypercalcemia and increased excretion of calcium in the urine. Rare forms of primary hyperparathyroidism include 1) hyperparathyroidism diagnosed in children or young adults and 2) hyperparathyroidism associated with germline mutations in susceptibility genes. The symptoms are mainly related to the level of serum calcium and/or to the kidney/urinary tract complications. In addition, the features associated with the genetic defects may also lead to the diagnosis.

Non-PTH Related Hypercalcemia

Hypercalcemia with low PTH is due to an excess in vitamin D action/concentration or to an increased efflux of calcium from the bone (hypophosphatasia, bone resorption due to PTHrP or cytokines production). The symptoms are mainly related to the level of serum calcium and/or to the kidney/urinary tract complications. Hypercalcemia due to anomalies in vitamin D metabolism is mainly diagnosed in neonates and young children with severe hypercalcemia and nephrocalcinosis. Hypophosphatasia may be diagnosed because of hypercalcelmia, hyperphosphatemia, low PTH and severely impaired bone mineralization.

Multiple endocrine neoplasia Type 1

Multiple endocrine neoplasia Type 1 (MEN1) is characterized by the development of neuroendocrine tumors of the parathyroid, pancreas, and anterior pituitary gland, and less commonly the adrenal cortical gland, with other non-endocrine tumors in some patients. In individuals with MEN1, tumors can develop at any age and 95% of patients develop clinical symptoms by the 5th decade. Parathyroid tumors causing hyperparathyroidism occur most commonly, and are often the first clinical manifestation of the disease.

Multiple Endocrine Neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN2) is characterized by the occurrence of medullary thyroid carcinoma, pheochromocytoma and, in one variant, primary hyperparathyroidism. The clinical manifestations of MEN2 are related to the syndrome subtypes and depend on the specific mutation in the RET gene. MEN2 can affect all age groups, with manifestations beginning in infancy to early childhood (MEN2B) or adulthood

Parathyroid cancer

Parathyroid cancer usually manifests as severe hypercalcemia, i.e. anorexia, polyuria, fatigue, dehydration, bone pain, subcortical bone resorption, pathological fractures and renal complications of hypercalciuria. A mass may be palpable in the neck.

Familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is a generally asymptomatic genetic disorder of phosphate and calcium metabolism characterized by lifelong moderate hypercalcemia along with normo- or hypocalciuria and elevated plasma parathyroid hormone (PTH) concentration. FHH is biologically characterized by moderate but significant hypercalcemia associated with levels of PTH and urinary calcium excretion that appear inappropriate in the presence of the hypercalcemia: serum levels of PTH are, in general, normal or slightly increased and calciuria is low. FHH is usually asymptomatic but rarely symptoms of fatigue, weakness, excessive thirst and concentration problems are experienced.


Hypoparathyroidism is due to the lack of production/secretion of PTH. It is characterized by low calcium, high phosphate and low PTH. Symptoms are mainly related to low levels of calcium can include: paresthesias, numbness, seizures and tetany (including muscle twitches and hand and foot spasms); in severe cases, hypocalcemia leads to cardiac complications. Long-term complications are frequent such as tissues calcifications, nephrocalcinosis, cognitive and neuropsychiatric difficulties. In children, hypoparathyroidism is mainly due to the impaired development of parathyroid glands; in adolescents and adults, hypoparathyroidism may be due to autοimmune diseases, drug side-effects and neck surgery


Disease definition

The term PHP (describes disorders that share common biochemical features of hypoparathyroidism (i.e.hypocalcaemia and hyperphosphataemia) that are the result of resistance of target tissues to the biological actions of PTH. Patients with PHP1A and PHP1C are also characterized by the variable expression of a collection of physical features, termed Albright hereditary osteodystrophy (AHO). Furthermore, based on the number of AHO features and the presence and extent of ectopic ossifications, patients might be classified as having pseudo-pseudohypoparathyroidism (PPHP; OMIM #612463), progressive osseous heteroplasia (POH; OMIM #166350) or osteoma cutis. Acrodysostosis (OMIM #101800) refers to a group of chondrodysplasias that resemble PHP in some patients, owing to the presence of brachydactyly and often resistance to different hormones, but differ from PHP owing to more extensive facial dysmorphism, nasal hypoplasia and often developmental delay.


The exact prevalence of PHP is unknown. Studies published in 2000 and 2016 estimated the prevalence to be 0.34 in 100,000 in Japan and 1.1 in 100,000 in Denmark. The prevalence of POH has never been estimated. However, it seems to be extremely rare, as <60 cases have been reported worldwide up to December 2016. The prevalence of Acrodysostosis is unknown as clinical, biochemical and radiological features overlap with those of PHP1A and PPHP.

Clinical description

All forms of PHP can present in infancy, especially if significant hypocalcemia occurs. Symptoms related to low levels of calcium include: paresthesias, numbness, seizures and tetany (including muscle twitches and hand and foot spasms). Some forms of PHP may remain unnoticed if patients do not have hypocalcemia and/or characteristic physical features, which include short stature, rounded face, short neck, brachydactyly, ectopic ossifications and other poorly defined abnormalities, collectively termed Albright hereditary osteodystrophy (AHO).


All patients with PHP and PHP-related disorders in whom a molecular diagnosis is confirmed have genetic or epigenetic alterations in genes encoding for proteins involved in the PTH/PTHrP signaling pathway. PHP1A, PPHP and POH are due to genetic defects in the gene coding the alpha sub-unit of the stimulatory G protein (GNAS, 20q13.2-q13.3).

Diagnostic methods

The diagnosis is based on the presence of characteristic clinical and endocrinological findings.

Genetic counseling

PHP can be sporadic or inherited autosomal dominantly with parental imprinting. In inherited cases, genetic counseling is possible.

Management and treatment

A multidisciplinary follow-up and early, specific interventions are necessary for efficient therapeutic management of these patients.

Management consists of general measures (lifestyle advice for obesity, exercise and rehabilitation) and specific measures aimed to correct hypocalcemia, growth retardation and other endocrine deficiencies. Surgical management may include orthopaedic, spinal and dental aspects.


Very variable depending on age at onset, severity and presence or absence of endocrine abnormalities.

Hereditary forms of Hypophosphatemic Rickets

Phosphate wasting leads to hypophosphatemia hence osteomalacia, rickets, mineralization defects, bone deformities, bone pain, poor growth, anomalies of teeth mineralization and muscle function impairment. Additional features may include nephrocalcinosis, craniosynostosis, hearing impairment, Chiari type 1 malformations, entesopathies and hyperparathyroidism. Hypophosphatemia associated with phosphate wasting is usually diagnosed in young children, yet the features are so variable that diagnosis may be reached only in adults or parents of affected patients. Hypophosphatemia associated with phosphate wasting is caused by genetic conditions leading to an increased production/action of the hormone FGF23. In rare cases, the low phosphate level is due to anomalies in the renal phosphate transport (genetic or acquired).

Acquired Oncogenic Osteomalacia

Oncogenic hypophosphatemia or Tumor Induced Osteomalacia (TIO) leads to severe hypophosphatemia and phosphate wasting due to a tumoral secretion of FGF23 by mesenchymal tumors; the calcium level is also usually low. Patients (usually adults) present with severe muscular defects, fractures, pseudofractures, bone and muscular pain. It is crucial to localize the source of FGF23 secretion through the best available imaging techniques.


Hyperphosphatemia may be due to the impaired excretion of urinary phosphate. Most cases are of genetic origin and are characterized by a lack of FGF23 secretion. Patients may present with joints and bone pain, diaphysitis and often severe ectopic calcifications.


Fibrous Dysplasia


The exact prevalence of fibrous dysplasia is unknown, but it is less than 1:2000.FD/MAS is a rare disorder characterized by skeletal lesions, skin hyperpigmentation, and hyper-functioning endocrinopathies


It arises from post-zygotic gain-of-function mutations in the GNAS gene, which encodes the α-subunit of the Gs signaling protein. These mutations disrupt the intrinsic GTPase activity of Gsα, leading to persistent stimulation of adenylyl cyclase and dysregulated production of cyclic AMP and downstream signaling. The resulting disease is mosaic with a broad clinical spectrum, ranging from a trivial incidentally discovered radiographic finding to severe and disabling disease.

Diagnostic methods

A diagnosis of the subtypes of FD/MAS can only be made after a thorough evaluation of a) the extent of skeletal disease: monostotic/polyostotic and b) the presence of extra-skeletal manifestations. Monostotic fibrous dysplasia is defined as the presence of fibrous dysplasia in one skeletal site only. Polyostotic fibrous dysplasia is defined as the presence of fibrous dysplasia in more than one skeletal site without extra-skeletal manifestations. McCune-Albright syndrome is defined as the combination of FD and one or more extra-skeletal feature, OR the presence of two or more extra skeletal features. Not requiring FD for the diagnosis of MAS reflects better understanding of the molecular pathogenesis of the disorder.

Mazabraud Syndrome is the combination of FD with intramuscular myxoma(s).

Management and treatment

Management consists of general measures (Provision of information about the disease, Lifestyle advice, Exercise and rehabilitation) and specific measures including management of FGF-23 induced renal phosphate wasting, Scoliosis, bone pain, Mazabraud syndrome, endocrinopathies of the ovary, testes, thyroid, pituitary and adrenals, haematological manifestations, gastrointestinal manifestations and increased risk of malignancy. Surgical management includes orthopaedic, spinal, craniofacial, maxillofacial and dental aspects.


Very variable depending on severity and response to drug and surgical treatment.

Osteogenesis Imperfecta

Disease definition

Osteogenesis imperfecta (OI) comprises a heterogeneous group of genetic disorders characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures with variable severity.


Brittle bone disease, Glass bone disease, Lobstein disease, OI, Osteopsathyrosis


Prevalence is estimated at between 1/10,000 and 1/20,000.

Clinical description

Age at diagnosis depends on the severity of the disease. Five clinically distinct types of OI have been identified. The most clinically relevant characteristic of all types of OI is bone fragility, which manifests as multiple spontaneous fractures. Osteogenesis imperfecta type II is lethal, type III is severe, types IV and V are moderate, and type I is mild (see these terms). Type I is nondeforming with normal height or mild short stature, blue sclera, and no dentinogenesis imperfecta (DI; see this term). Patients with type II present multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density on skull X-rays, and dark sclera. The main signs of type III include very short stature, a triangular face, severe scoliosis, grayish sclera, and DI. Patients with type IV have moderately short stature, mild to moderate scoliosis, grayish or white sclera, and DI. Type V is characterized by mild to moderate short stature, dislocation of the radial head, mineralized interosseous membranes, hyperplastic callus, white sclera, and no DI. Other genetically different types have been observed (types VI to IX) but they are not clinically different from types II-IV.


In 95% of cases, OI is caused by mutations in the COL1A1 and COL1A2 genes (17q21.33 and 7q21.3) encoding the alpha1 and alpha2 chains of type 1collagen. These mutations can cause all five clinical types of OI. Transmission is autosomal dominant. Autosomal recessive forms of OI are also observed and are caused by mutations in the LEPRE1, CRTAP, and PPIB genes (1p34.1, 3p22 and 15q21-q22). Autosomal recessive forms are always severe forms with severe hypotonia.

Diagnostic methods

Diagnosis is based on skeletal and extra-skeletal clinical findings. Radiological studies reveal osteoporosis and the presence of wormian-like bones. Bone densitometry confirms the low bone mass.

Differential diagnosis

Differential diagnoses include in utero diagnosis of chondrodysplasia, idiopathic juvenile osteoporosis, osteoporosis-pseudoglioma syndrome, Cole-Carpenter and Bruck syndromes, hyper or hypophosphatasia, panostotic form of polyostotic fibrous dysplasia (see these terms), non-accidental injury (multiple fractures without osteoporosis), and osteoporosis due to medication, nutritional deficiency, metabolic disease, or leukemia. The presence of several fractures should not lead to the assumption of child abuse.

Management and treatment

Management should be multidisciplinary involving experienced medical, orthopedic, physiotherapy and rehabilitation specialists. Bisphosphonates with potent antiresorptive properties are now considered as the standard of care for severe forms but do not constitute a cure. Prevention of vitamin D and calcium deficiency is essential throughout life. Surgical management is essential for the correction of bone and spinal deformities and the prevention of long bone fractures (centro-medullary osteosynthesis). Early physiotherapy improves autonomy by helping to evaluate any motor deficits, reducing the risk of falls and encouraging patients to take up a sporting activity.


Functional prognosis depends on the severity of the disease and on the quality of management. Vital prognosis depends on the severity of any respiratory complications associated with spinal deformities.


Hypophosphatasia (HPP) is a rare heritable metabolic disorder characterized by defective mineralization of bone and/or teeth in the presence of reduced activity of unfractionated serum alkaline phosphatase (ALP). The clinical spectrum is extremely wide, from stillbirth at one end to fractures of the lower extremities in adulthood, at the other, or even no bone manifestations (odontohypophosphatasia).


Exact prevalence and incidence data for hypophosphatasia are not available. The prevalence ofsevere forms of the disease has been estimated to be 1/300,000 births in Europe.

Clinical description

Six different clinical forms of HPP have been described. Prenatal benign hypophosphatasia involves prenatal skeletal manifestations that slowly resolve to become the milder childhood or adult form. Perinatal lethal hypophosphatasia involves significant hypomineralization and leads to hypercalcemia and respiratory insufficiency. Infantile hypophosphatasia is characterized by rickets developing between birth and six months of age. Childhood-onset hypophosphatasia ranges from low bone mineral density with unexplained fractures to rickets. Adult hypophosphatasia involves early loss of adult dentition and stress fractures of the lower extremities in middle age. Lastly, odontohypophosphatasia includes premature exfoliation of primary teeth and/or severe dental caries. Rare cases of infantile hypophosphatasia that have normal serum alkaline phosphatase activity are known as ”pseudohypophosphatasia”.


More than 250 different mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The gene encodes alkaline phosphatase, tissue-nonspecific isozyme (TNSALP) involved in skeletal mineralization.

Diagnostic methods

The diagnosis is based on laboratory testing and molecular genetic testing of the ALPL gene to detect causative mutations. Serum alkaline phosphatase (AP) activity is markedly reduced while urinary phosphoethanolamine (PEA) is increased but these abnormalities are not pathognomonic. Ultrasound is used in prenatal and perinatal forms. Clinical examinations and radiographs help to establish the diagnosis in infantile, childhood and adult forms.

Differential diagnosis

The differential diagnosis includes osteogenesis imperfecta and campomelic dysplasia in early diagnosis, and hypophosphatemic rickets and achondrogenesis in later diagnosis (see these terms).

Genetic counseling

Perinatal and severe infantile HPP are inherited as autosomal recessive traits. Prenatal benign, moderate infantile, childhood HPP, adult HPP and odontohypophosphatasia can be inherited in an autosomal recessive or autosomal dominant manner, depending on the specific effect the gene mutation has on TNSALP activity. The less severe the disease, the more likely it is dominantly inherited. The range of inheritance patterns partially explains the clinical heterogeneity. In autosomal recessive hypophosphatasia, rare de novo mutations have been reported. In autosomal dominant hypophosphatasia, affected patients may have an affected parent but penetrance appears to be low and de novo mutations have not been reported. HPP displays highly variable expressivity. Genetic counseling is complicated by these factors but should be offered to affected families.

Management and treatment

Supportive symptomatic treatment in childhood and adult forms includes non-steroidal anti-inflammatory drugs (children), teriparatide (adults) and orthopedic management.

Dental monitoring and care are essential. Enzyme replacement therapy also plays a role. Bisphosphonates are generally contraindicated in hypophosphatasia.


The perinatal form is almost always fatal within days or weeks. Respiratory complications lead to high mortality rates in the infantile form. Life expectancy is not thought to be affected in the adult form or in odontohypophosphatasia


Research Activity-Publications


  1.  Gender Predilection in Sporadic Parathyroid Adenomas Yavropoulou MP, Anastasilakis AD, Panagiotakou A, Kassi E, Makras P . Int J Mol Sci. 2020 Apr 22;21(8):2964. doi: 10.3390/ijms21082964 https://pubmed.ncbi.nlm.nih.gov/32331456/
  2. Management of parathyroid disorders: recommendations of the working group of the Bone Section of the Hellenic Endocrine Society.Makras P, Yavropoulou MP, Kassi E, Anastasilakis AD, Vryonidou A, Tournis S.Hormones (Athens). 2020 Apr 15. doi: 10.1007/s42000-020-00195-w. https://pubmed.ncbi.nlm.nih.gov/32297171/
  3. Hypercalcitoninaemia in pseudohypo-parathyroidism type 1A and type 1B. Yavropoulou MP, Chronopoulos E, Trovas G, Avramidis E, Elli FM, Mantovani G, Zebekakis P, Yovos JG.Endocrinol Diabetes Metab Case Rep. 2019 Jan 31;2019:18-0125. doi: 10.1530/EDM-18-0125. https://pubmed.ncbi.nlm.nih.gov/30703064/
  4. A Role for Circular Non-Coding RNAs in the Pathogenesis of Sporadic Parathyroid Adenomas and the Impact of Gender-Specific Epigenetic Regulation. Yavropoulou MP, Poulios C, Michalopoulos N, Gatzou A, Chrisafi S, Mantalovas S, Papavramidis T, Daskalaki E, Sofou E, Kotsa K, Kesisoglou I, Zebekakis P, Yovos JG.Cells. 2018 Dec 30;8(1):15. doi: 10.3390/cells8010015. https://pubmed.ncbi.nlm.nih.gov/30598042/
  5. Hypoparathyroidism: is it that easy to treat? Triantafyllou E, Yavropoulou MP, Anastasilakis AD, Makras P.Hormones (Athens). 2019 Mar;18(1):55-63. doi: 10.1007/s42000-018-0032-6. Epub 2018 Jun 6.PMID: 29876797 https://pubmed.ncbi.nlm.nih.gov/29876797/
  6. Distant lung metastases caused by a histologically benign phosphaturic mesenchymal tumor. Yavropoulou MP, Poulios C, Foroulis C, Tournis S, Hytiroglou P, Kotsa K, Kessisoglou I, Zebekakis P.Endocrinol Diabetes Metab Case Rep. 2018 May 16;2018:18-0023. doi: 10.1530/EDM-18-0023. eCollection 2018. https://pubmed.ncbi.nlm.nih.gov/29785270/
  7. PTH and PTHR1 in osteocytes. New insights into old partners. Yavropoulou MP, Michopoulos A, Yovos JG.Hormones (Athens). 2017 Apr;16(2):150-160. doi: 10.14310/horm.2002.1730.PMID: 28742503 Review. https://pubmed.ncbi.nlm.nih.gov/28742503/
  8. Severe osteoporosis with multiple spontaneous vertebral fractures in a young male carrying triple polymorphisms in the vitamin D receptor, collagen type 1, and low-density lipoprotein receptor-related peptide 5 genes. Yavropoulou MP, Kollia P, Chatzidimitriou D, Samara S, Skoura L, Yovos JG.Hormones (Athens). 2016 Oct;15(4):551-556. doi:10.14310/horm.2002.1710. https://pubmed.ncbi.nlm.nih.gov/28222408/
  9. Tumor-induced osteomalacia due to a recurrent mesenchymal tumor overexpressing several growth factor receptors. Yavropoulou MP, Gerothanasi N, Frydas A, Triantafyllou E, Poulios C, Hytiroglou P, Apostolou P, Papasotiriou I, Tournis S, Kesisoglou I, Yovos JG.Endocrinol Diabetes Metab Case Rep. 2015;2015:150025. doi: 10.1530/EDM-15-0025https://pubmed.ncbi.nlm.nih.gov/26155363/
  10. The PRIMARA study: a prospective, descriptive, observational study to review cinacalcet use in patients with primary hyperparathyroidism in clinical practice. Schwarz P, Body JJ, Cáp J, Hofbauer LC, Farouk M, Gessl A, Kuhn JM, Marcocci C, Mattin C, Muñoz Torres M, Payer J, Van De Ven A, Yavropoulou M, Selby P.Eur J Endocrinol. 2014 Dec;171(6):727-35. doi: 10.1530/EJE-14-0355. https://pubmed.ncbi.nlm.nih.gov/25240499/
  11. Serum sclerostin levels in Paget’s disease and prostate cancer with bone metastases with a wide range of bone turnover. Yavropoulou MP, van Lierop AH, Hamdy NA, Rizzoli R, Papapoulos SE.Bone. 2012 Jul;51(1):153-7 doi10.1016/j.bone.2012.04.016. https://pubmed.ncbi.nlm.nih.gov/22579776/
  12. Cinacalcet in hyperparathyroidism secondary to X-linked hypophosphatemic rickets: case report and brief literature review. Yavropoulou MP, Kotsa K, Gotzamani Psarrakou A, Papazisi A, Tranga T, Ventis S, Yovos JG.Hormones (Athens). 2010 Jul-Sep;9(3):274-8. doi: 10.14310/horm.2002.12 https://pubmed.ncbi.nlm.nih.gov/20688626/
  13. Identification of Patients at High Risk for Postsurgical Hypoparathyroidism. Kakava K, Tournis S, Makris K, Papadakis G, Kassi E, Dontas I, Karatzas T.In Vivo. 2020 Sep-Oct;34(5):2973-2980.doi:10.21873/invivo.12128.  https://pubmed.ncbi.nlm.nih.gov/32871840/
  14. Fibroblast Growth Factor 23 (FGF23) and Klotho Protein in Beta-Thalassemia. Stefanopoulos D, Nasiri-Ansari N, Dontas I, Vryonidou A, Galanos A, Psaridi L, Fatouros IG, Mastorakos G, Papavassiliou AG, Kassi E, Tournis S. https://pubmed.ncbi.nlm.nih.gov/32215890/
  15. Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature. Asonitis N, Angelousi A, Zafeiris C, Lambrou GI, Dontas I, Kassi E. Horm Metab Res. 2019 Dec;51(12):770-778.doi: 10.1055/a-1049-0647. https://pubmed.ncbi.nlm.nih.gov/31826272/
  16. Postsurgical Hypoparathyroidism: A Systematic Review. Kakava K, Tournis S, Papadakis G, Karelas I, Stampouloglou P, Kassi E, Triantafillopoulos I, Villiotou V, Karatzas T. https://pubmed.ncbi.nlm.nih.gov/27107072/
  17. Hypercalcemia of malignancy treated with cinacalcet. Asonitis N, Kassi E, Kokkinos M, Giovanopoulos I, Petychaki F, Gogas H.Endocrinol Diabetes Metab Case Rep. 2017 Dec 15;2017:17-0118. doi: 10.1530/EDM-17-0118. https://pubmed.ncbi.nlm.nih.gov/29399364/
  18. Treatment of severe hypocalcaemia due to osteoblastic metastases in a patient with post-thyroidectomy hypoparathyroidism with 153Sm-EDTMP.Kassi E, Kapsali I, Kokkinos M, Gogas H.BMJ Case Rep. 2017 May 16;2017:bcr2017219354. doi: 10.1136/bcr-2017-219354 https://pubmed.ncbi.nlm.nih.gov/28512123/
  1. A novel mutation of the calcium-sensing receptor gene in a Greek family from Nisyros. Zapanti E, Polonifi A, Kokkinos M, Boutzios G, Kassi G, Nasiri Ansari N, Kassi E, Polyzos A. Hormones (Athens). 2015 Apr-Jun;14(2):321-5. doi: 10.14310/horm.2002.1586. PMID: 26158657. http://www.hormones.gr/8569/article/article.html

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