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Hajdu-Cheney syndrome(HJCYS)

MedGen UID:
182961
Concept ID:
C0917715
Disease or Syndrome
Synonyms: Acroosteolysis dominant type; Acroosteolysis with osteoporosis and changes in skull and mandible; Arthrodentoosteodysplasia; Cheney syndrome; HJCYS; SERPENTINE FIBULA-POLYCYSTIC KIDNEY SYNDROME
SNOMED CT: Hajdu-Cheney syndrome (63122002); Arthro-dento-osteo dysplasia (63122002); Cheney syndrome (63122002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): NOTCH2 (1p12)
 
Monarch Initiative: MONDO:0007057
OMIM®: 102500
Orphanet: ORPHA955

Definition

Hajdu-Cheney syndrome (HJCYS) is a rare autosomal dominant skeletal disorder characterized by short stature, coarse and dysmorphic facies, bowing of the long bones, and vertebral anomalies. Facial features include hypertelorism, bushy eyebrows, micrognathia, small mouth with dental anomalies, low-set ears, and short neck. There is progressive focal bone destruction, including acroosteolysis and generalized osteoporosis. Additional and variable features include hearing loss, renal cysts, and cardiovascular anomalies (summary by Ramos et al., 1998; Simpson et al., 2011; Isidor et al., 2011). [from OMIM]

Additional description

From MedlinePlus Genetics
Hajdu-Cheney syndrome is a rare disorder that can affect many parts of the body, particularly the bones. Loss of bone tissue from the hands and feet (acro-osteolysis) is a characteristic feature of the condition. The fingers and toes are short and broad, and they may become shorter over time as bone at the tips continues to break down. Bone loss in the fingers can interfere with fine motor skills, such as picking up small objects.

Bone abnormalities throughout the body are common in Hajdu-Cheney syndrome. Affected individuals develop osteoporosis, which causes the bones to be brittle and prone to fracture. Many affected individuals experience breakage (compression fractures) of the spinal bones (vertebrae). Some also develop abnormal curvature of the spine (scoliosis or kyphosis). Hajdu-Cheney syndrome also affects the shape and strength of the long bones in the arms and legs. The abnormalities associated with this condition lead to short stature.

Hajdu-Cheney syndrome also causes abnormalities of the skull bones, including the bones of the face. The shape of the skull is often described as dolichocephalic, which means it is elongated from back to front. In many affected individuals, the bone at the back of the skull bulges outward, causing a bump called a prominent occiput. Distinctive facial features associated with this condition include widely spaced and downward-slanting eyes, eyebrows that grow together in the middle (synophrys), low-set ears, a sunken appearance of the middle of the face (midface hypoplasia), and a large space between the nose and upper lip (a long philtrum). Some affected children are born with an opening in the roof of the mouth called a cleft palate or with a high arched palate. In affected adults, the facial features are often described as "coarse."

Other features of Hajdu-Cheney syndrome found in some affected individuals include joint abnormalities, particularly an unusually large range of joint movement (hypermobility); dental problems; hearing loss; a deep, gravelly voice; excess body hair; recurrent infections in childhood; heart defects; and kidney abnormalities such as the growth of multiple fluid-filled cysts (polycystic kidneys). Some people with this condition have delayed development in childhood, but the delays are usually mild.

The most serious complications of Hajdu-Cheney syndrome, which occur in about half of all affected individuals, are abnormalities known as platybasia and basilar invagination. Platybasia is a flattening of the base of the skull caused by thinning and softening of the skull bones. Basilar invagination occurs when the softened bones allow part of the spine to protrude abnormally through the opening at the bottom of the skull, pushing into the lower parts of the brain. These abnormalities can lead to severe neurological problems, including headaches, abnormal vision and balance, a buildup of fluid in the brain (hydrocephalus), abnormal breathing, and sudden death.

The signs and symptoms of Hajdu-Cheney syndrome vary greatly among affected individuals, even among members of the same family. Many of the disorder's features, such as acro-osteolysis and some of the characteristic facial features, are not present at birth but become apparent in childhood or later. The risk of developing platybasia and basilar invagination also increases over time.

The features of Hajdu-Cheney syndrome overlap significantly with those of a condition called serpentine fibula-polycystic kidney syndrome (SFPKS). Although they used to be considered separate disorders, researchers discovered that the two conditions are associated with mutations in the same gene. Based on these similarities, many researchers now consider Hajdu-Cheney syndrome and SFPKS to be variants of the same condition.  https://medlineplus.gov/genetics/condition/hajdu-cheney-syndrome

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Polycystic kidney disease
MedGen UID:
9639
Concept ID:
C0022680
Disease or Syndrome
The presence of multiple cysts in both kidneys.
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Renal cyst
MedGen UID:
854361
Concept ID:
C3887499
Disease or Syndrome
A fluid filled sac in the kidney.
Dislocated radial head
MedGen UID:
488814
Concept ID:
C0265563
Congenital Abnormality
A dislocation of the head of the radius from its socket in the elbow joint.
Genu valgum
MedGen UID:
154364
Concept ID:
C0576093
Anatomical Abnormality
The legs angle inward, such that the knees are close together and the ankles far apart.
Acroosteolysis
MedGen UID:
183017
Concept ID:
C0917990
Disease or Syndrome
Dissolution or degeneration of bone tissue of the phalanges of the hand.
Crowded carpal bones
MedGen UID:
350140
Concept ID:
C1863317
Finding
Fibular bowing
MedGen UID:
869374
Concept ID:
C4023801
Anatomical Abnormality
A bending or abnormal curvature of the fibula.
Foot acroosteolysis
MedGen UID:
871259
Concept ID:
C4025744
Pathologic Function
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Intestinal malrotation
MedGen UID:
113153
Concept ID:
C0221210
Congenital Abnormality
An abnormality of the intestinal rotation and fixation that normally occurs during the development of the gut. This can lead to volvulus, or twisting of the intestine that causes obstruction and necrosis.
Conductive hearing impairment
MedGen UID:
9163
Concept ID:
C0018777
Disease or Syndrome
An abnormality of vibrational conductance of sound to the inner ear leading to impairment of sensory perception of sound.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Large earlobe
MedGen UID:
334979
Concept ID:
C1844573
Finding
Increased volume of the earlobe, that is, abnormally prominent ear lobules.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Pathologic fracture
MedGen UID:
42095
Concept ID:
C0016663
Pathologic Function
A pathologic fracture occurs when a bone breaks in an area that is weakened secondarily to another disease process such as tumor, infection, and certain inherited bone disorders. A pathologic fracture can occur without a degree of trauma required to cause fracture in healthy bone.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
Protrusion of the contents of the abdominal cavity through the inguinal canal.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Vertebral compression fracture
MedGen UID:
75497
Concept ID:
C0262431
Finding
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Absent frontal sinuses
MedGen UID:
343405
Concept ID:
C1855669
Finding
Aplasia of frontal sinus.
Biconcave vertebral bodies
MedGen UID:
383834
Concept ID:
C1856087
Finding
Exaggerated concavity of the anterior or posterior surface of the vertebral body, i.e., the upper and lower vertebral endplates are hollowed inward.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Finding
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Elongated sella turcica
MedGen UID:
354951
Concept ID:
C1863311
Finding
Tall lumbar vertebral bodies
MedGen UID:
350137
Concept ID:
C1863313
Finding
Cervical instability
MedGen UID:
350138
Concept ID:
C1863314
Finding
Wormian bones
MedGen UID:
766814
Concept ID:
C3553900
Congenital Abnormality
The presence of extra bones within a cranial suture. Wormian bones are irregular isolated bones which appear in addition to the usual centers of ossification of the cranium.
Basilar impression
MedGen UID:
1639127
Concept ID:
C4551802
Congenital Abnormality
Abnormal elevation of the floor of the posterior fossa including occipital condyles and foramen magnum.
Dental malocclusion
MedGen UID:
9869
Concept ID:
C0024636
Anatomical Abnormality
Dental malocclusion refers to an abnormality of the occlusion, or alignment, of the teeth and the way the upper and lower teeth fit together, resulting in overcrowding of teeth or in abnormal bite patterns.
Narrow mouth
MedGen UID:
44435
Concept ID:
C0026034
Congenital Abnormality
Distance between the commissures of the mouth more than 2 SD below the mean. Alternatively, an apparently decreased width of the oral aperture (subjective).
Premature loss of teeth
MedGen UID:
66678
Concept ID:
C0232513
Finding
Exfoliation of a tooth more than 2 SD earlier than the normal age for the deciduous teeth and not related to traume or neglect. Exfoliation of a permanent tooth is per se abnormal.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Wide nose
MedGen UID:
140869
Concept ID:
C0426421
Finding
Interalar distance more than two standard deviations above the mean for age, i.e., an apparently increased width of the nasal base and alae.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
Full cheeks
MedGen UID:
355661
Concept ID:
C1866231
Finding
Increased prominence or roundness of soft tissues between zygomata and mandible.
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
Short nail
MedGen UID:
140850
Concept ID:
C0423808
Finding
Decreased length of nail.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Iris coloboma
MedGen UID:
116097
Concept ID:
C0240063
Anatomical Abnormality
A coloboma of the iris.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHajdu-Cheney syndrome

Professional guidelines

PubMed

Efstathiadou ZA, Kostoulas C, Polyzos SA, Adamidou F, Georgiou I, Kita M
Endocrine 2021 Jan;71(1):208-215. Epub 2020 Aug 9 doi: 10.1007/s12020-020-02446-7. PMID: 32772338
Herd RS, Sprung J, Weingarten TN
Paediatr Anaesth 2015 Jul;25(7):727-37. Epub 2015 Mar 4 doi: 10.1111/pan.12643. PMID: 25736220
Sawin PD, Menezes AH
J Neurosurg 1997 Jun;86(6):950-60. doi: 10.3171/jns.1997.86.6.0950. PMID: 9171173

Recent clinical studies

Etiology

Kaczoruk-Wieremczuk M, Adamska P, Adamski ŁJ, Wychowański P, Jereczek-Fossa BA, Starzyńska A
Int J Environ Res Public Health 2021 Aug 28;18(17) doi: 10.3390/ijerph18179099. PMID: 34501688Free PMC Article
Duraiswamy G, Ashraf M, Sambandam SN, Shanmugasundaram S
JBJS Case Connect 2021 May 21;11(2) doi: 10.2106/JBJS.CC.20.00711. PMID: 34019492
Pittaway JFH, Harrison C, Rhee Y, Holder-Espinasse M, Fryer AE, Cundy T, Drake WM, Irving MD
Orphanet J Rare Dis 2018 Apr 4;13(1):47. doi: 10.1186/s13023-018-0795-5. PMID: 29618366Free PMC Article
Botou A, Bangeas A, Alexiou I, Sakkas LI
Clin Rheumatol 2017 Jan;36(1):9-14. Epub 2016 Oct 29 doi: 10.1007/s10067-016-3459-7. PMID: 27796661
O'Reilly MA, Shaw DG
Ann Rheum Dis 1994 Apr;53(4):276-9. doi: 10.1136/ard.53.4.276. PMID: 8203959Free PMC Article

Diagnosis

Ekure EN, Sokunbi O, Kruszka P, Muenke M, Adeyemo AA
Am J Med Genet A 2023 Jan;191(1):271-274. Epub 2022 Oct 27 doi: 10.1002/ajmg.a.63013. PMID: 36301051Free PMC Article
Zeng C, Lin Y, Lu Z, Chen Z, Jiang X, Mao X, Liu Z, Lu X, Zhang K, Yu Q, Wang X, Huang Y, Liu L
BMC Musculoskelet Disord 2020 Mar 6;21(1):154. doi: 10.1186/s12891-020-3181-0. PMID: 32143606Free PMC Article
Regev M, Pode-Shakked B, Jacobson JM, Raas-Rothschild A, Goldstein DB, Anikster Y
Eur J Med Genet 2019 Jan;62(1):35-38. Epub 2018 Apr 23 doi: 10.1016/j.ejmg.2018.04.015. PMID: 29698804
Canalis E, Zanotti S
Orphanet J Rare Dis 2014 Dec 10;9:200. doi: 10.1186/s13023-014-0200-y. PMID: 25491639Free PMC Article
O'Reilly MA, Shaw DG
Ann Rheum Dis 1994 Apr;53(4):276-9. doi: 10.1136/ard.53.4.276. PMID: 8203959Free PMC Article

Therapy

Polyzos SA, Makras P, Tournis S, Anastasilakis AD
Bone 2019 Dec;129:115048. Epub 2019 Aug 24 doi: 10.1016/j.bone.2019.115048. PMID: 31454537
Woon CYL, Mardjetko SM
Eur Spine J 2018 Jul;27(Suppl 3):403-408. Epub 2017 Nov 4 doi: 10.1007/s00586-017-5373-3. PMID: 29103128
Sakka S, Gafni RI, Davies JH, Clarke B, Tebben P, Samuels M, Saraff V, Klaushofer K, Fratzl-Zelman N, Roschger P, Rauch F, Högler W
J Clin Endocrinol Metab 2017 Nov 1;102(11):4163-4172. doi: 10.1210/jc.2017-01102. PMID: 28938420Free PMC Article
Adami G, Rossini M, Gatti D, Orsolini G, Idolazzi L, Viapiana O, Scarpa A, Canalis E
Bone 2016 Nov;92:150-156. Epub 2016 Aug 31 doi: 10.1016/j.bone.2016.08.025. PMID: 27592446Free PMC Article
Canalis E, Zanotti S
Orphanet J Rare Dis 2014 Dec 10;9:200. doi: 10.1186/s13023-014-0200-y. PMID: 25491639Free PMC Article

Prognosis

Deb W, Joubert M, Cogné B, Vincent M, Ghesh L, Bézieau S, Le Vaillant C, Beneteau C
Eur J Med Genet 2023 Jul;66(7):104769. Epub 2023 Apr 28 doi: 10.1016/j.ejmg.2023.104769. PMID: 37121269
Jirečková J, Magner M, Lambert L, Baxová A, Leiská A, Kopečková L, Fajkusová L, Zeman J
Prague Med Rep 2018;119(4):156-164. doi: 10.14712/23362936.2019.3. PMID: 30779700
Pittaway JFH, Harrison C, Rhee Y, Holder-Espinasse M, Fryer AE, Cundy T, Drake WM, Irving MD
Orphanet J Rare Dis 2018 Apr 4;13(1):47. doi: 10.1186/s13023-018-0795-5. PMID: 29618366Free PMC Article
Palav S, Vernekar J, Pereira S, Desai A
J Radiol Case Rep 2014 Sep;8(9):1-8. Epub 2014 Sep 30 doi: 10.3941/jrcr.v8i9.1833. PMID: 25426244Free PMC Article
O'Reilly MA, Shaw DG
Ann Rheum Dis 1994 Apr;53(4):276-9. doi: 10.1136/ard.53.4.276. PMID: 8203959Free PMC Article

Clinical prediction guides

Kaczoruk-Wieremczuk M, Adamska P, Adamski ŁJ, Wychowański P, Jereczek-Fossa BA, Starzyńska A
Int J Environ Res Public Health 2021 Aug 28;18(17) doi: 10.3390/ijerph18179099. PMID: 34501688Free PMC Article
Jirečková J, Magner M, Lambert L, Baxová A, Leiská A, Kopečková L, Fajkusová L, Zeman J
Prague Med Rep 2018;119(4):156-164. doi: 10.14712/23362936.2019.3. PMID: 30779700
Pittaway JFH, Harrison C, Rhee Y, Holder-Espinasse M, Fryer AE, Cundy T, Drake WM, Irving MD
Orphanet J Rare Dis 2018 Apr 4;13(1):47. doi: 10.1186/s13023-018-0795-5. PMID: 29618366Free PMC Article
Vollersen N, Hermans-Borgmeyer I, Cornils K, Fehse B, Rolvien T, Triviai I, Jeschke A, Oheim R, Amling M, Schinke T, Yorgan TA
J Bone Miner Res 2018 Jan;33(1):70-83. Epub 2017 Sep 20 doi: 10.1002/jbmr.3283. PMID: 28856714
Zhao W, Petit E, Gafni RI, Collins MT, Robey PG, Seton M, Miller KK, Mannstadt M
Osteoporos Int 2013 Aug;24(8):2275-81. Epub 2013 Feb 7 doi: 10.1007/s00198-013-2298-5. PMID: 23389697Free PMC Article

Recent systematic reviews

Cortés-Martín J, Díaz-Rodríguez L, Piqueras-Sola B, Rodríguez-Blanque R, Bermejo-Fernández A, Sánchez-García JC
Int J Environ Res Public Health 2020 Aug 25;17(17) doi: 10.3390/ijerph17176174. PMID: 32854429Free PMC Article

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