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ARTICLE IN PRESSG ModelONSOI-4188; No. of Pages 5

Joint Bone Spine xxx (2015) xxx–xxx

Available online at

ScienceDirectwww.sciencedirect.com

ase report

very rare cause of acro-osteolysis: Hajdu-Cheney syndrome

amille Deprouwa, Antoine Feydyb, Janine-Sophie Giraudet Le Quintreca,d,arbara Ruizc, André Kahana, Yannick Allanorea,∗,c

Service de rhumatologie A, hôpital Cochin, AP–HP, université Paris Descartes, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, FranceService de radiologie B, hôpital Cochin, AP–HP, université Paris Descartes, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, FranceInserm U1016 UMR 8104, hôpital Cochin, université Paris Descartes, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, FranceOrphanet – Inserm US14, plateforme maladies rares, 96, rue Didot, 75014 Paris, France

a r t i c l e i n f o

rticle history:ccepted 17 February 2015vailable online xxx

eywords:

a b s t r a c t

Acro-osteolysis is not uncommon and occurs in several conditions. Additional clinical and paraclinicalfindings and sometimes the performance of molecular tests can help to clarify the diagnosis. Here, wereport the case of a 36-year-old woman who was referred to our department because of acute painin the extremity of the left index finger. However, subsequent clinical examination also revealed short

cro-osteolysisajdu-Cheney syndromeOTCH2

digits with pseudo-clubbing related to acro-osteolysis. Furthermore, severe osteoporosis, a moderatedysmorphic face, joint hypermobility, biological variables within normal ranges and her clinical historyled us to consider the diagnosis of Hajdu-Cheney syndrome. Molecular analysis confirmed the diagnosiswith the identification of a mutation in the NOTCH2 gene. The patient received bisphosphonate therapy,which resulted in some clinical and biological improvement 12 months later.

© 2015 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie.

. Introduction

Acro-osteolysis refers to destructive lytic changes of the dis-al phalanges. It usually involves the hands but the feet can alsoe affected. Although resorption may be partial, more extensiveamage can promote the shortening of the fingers or toes. Acro-steolysis may be familial, non-familial and occupational.

Here, we report a case of severe acro-osteolysis. Clinical andadiographic findings of bone structure suggested the involvementf a congenital syndrome. In line with the above-mentioned abnor-alities, molecular analysis revealed a NOTCH2 mutation known to

ause Hajdu-Cheney syndrome.

. Case report

A 36-year-old woman was referred for hospitalisation due toain in the extremity of the left index finger. Since childhood,he patient had been aware of deformity in the left index fin-er, believed to be caused by whitlow, according to her parents.

Please cite this article in press as: Deprouw C, et al. A very rare caus(2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.013

owever, since the age of 10, she suffered from several fracturesithout trauma, including one fracture in the left foot and two in

he right wrist. In parallel, several of her teeth had shown abnormal

∗ Corresponding author.E-mail address: [email protected] (Y. Allanore).

http://dx.doi.org/10.1016/j.jbspin.2015.02.013297-319X/© 2015 Published by Elsevier Masson SAS on behalf of the Société Française d

mobility, leading to removal of three teeth during her teenage years.The failure of dental appliance, led to the use of dental implants atthe age of 20, preceded by alveolar bone reconstruction. In addi-tion, the patient underwent surgery to repair a cleft palate at theage of two, and to treat lumbar spondylolisthesis at the age of 12.She noticed some abnormalities (such as clubbing) of the tips of herfingers and toes.

She recently complained of inflammation in the left index fin-ger, involving erythema with pain that tended to come and go.At the time of physical examination, the joints were not swollenand the extremities were cold (but without Raynaud’s syndrome).The patient had short digits with digital pseudo-clubbing, mostlyinvolving the second and third fingers, hypoplasia of the toenails,mild generalized hypermobility, and moderate dysmorphic face:down-slanted palpebral fissures, low set ears, coarse hair, thickeyebrows, broad nose with forward nostrils (Fig. 1).

No haematological or immune abnormalities were identifiedand serum concentrations of acute phase reactants were withinnormal ranges (C-reactive protein: 1 mg/L, ESR: 2 mm at the 1sthour). Investigation of renal function revealed creatininemia of65 �mol/L and urea of 4.8 mmol/L. Blood and urine tests for bonediseases showed serum calcium levels of 2.30 mmol/L, serum ion-

e of acro-osteolysis: Hajdu-Cheney syndrome. Joint Bone Spine

ized calcium levels of 1.25 mmol/L, serum phosphates levels of1.17 mmol/L, alkaline phosphatase levels of 43 U/L, 25-OH-vitaminD levels of 72 nmol/L, parathyroid hormone levels of 1.80 pmol/L,urinary calcium levels of 0.4 mmol/L, urinary phosphates levels of

e Rhumatologie.

dx.doi.org/10.1016/j.jbspin.2015.02.013


http://www.sciencedirect.com/science/journal/1297319X

mailto:[email protected]


ARTICLE IN PRESSG ModelBONSOI-4188; No. of Pages 5

2 C. Deprouw et al. / Joint Bone Spine xxx (2015) xxx–xxx

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ig. 1. A. Photographs of the face: the patient has a moderate dysmorphic face: dowith forward nostrils. B. Photographs of the hands showing short digits and distal c

.1 mmol/L, osteocalcin levels of 18 ng/mL (norm 11–27), and CTXevels of 391 pg/mL (norm 25–573).

The X-ray revealed symmetric distal phalanx osteolysis on alloes and essentially on the first three fingers on hands, subchon-ral bone resorption of the fifth metatarsophalangeal and proximal

nterphalangeal right foot joints, non-union (on fracture) of thefth left metatarsal. Furthermore, computed tomography of theands with 2D and 3D images showed the extension of acro-steolysis on several fingers (Fig. 2). Dorsal and lumbar vertebraeere biconcave, and the stage 2–3 L5 spondylolisthesis with poste-

ior arthrodesis was visible on radiographs (not shown). A delayedssification of occipito-parietal suture was present on skull radio-raphs (not shown). The bone mineral density of the spine was veryow with a lumbar spine T-score of −4.2 SD and total hip T-scoref −1.6 SD. Capillaroscopy was normal and cardiac and abdominalltrasound examinations excluded birth defects.

The association of clinical and paraclinical findings and theatient’s medical history led us to consider the diagnosis of Hajdu-heney syndrome. All 34 exons and exon-intron boundaries of theOTCH2 gene were sequenced and McVector® software was used


o search for mutation and polymorphisms based on the publishedOTCH2 sequence on chromosome 1 (genebank accession num-er: NG 008163). The primer pairs were chosen at approximately00 bp surrounding each exon boundary. DNA sequencing was

nted palpebral fissures, low set ears, coarse hair, thick eyebrows, and a broad noseg of third fingers.

performed using thermostable DNA polymerase from Larova Bio-chemic GmbH (Germany) on GeneAmp® PCR system 9600 (PerkinElmer). Primer sequences and conditions of amplification are avail-able on request. Fluorescent sequencing was carried-out with BigDye Terminator version 1.0 on GeneAmp® PCR System 9700 (PerkinElmer) under conditions supplied by the manufacturer. Electro-pherograms were analysed using Sequencing Analysis® 3.4 andSeqED® software. PCR amplification and sequencing showed amutation in exon 34 of the NOTCH2 gene: mutation Q2223X C > T(Fig. 3). Exon 34 is the last exon of the NOTCH2 gene, and codesfor the C-terminal part of the protein. The mutation results in apremature stop codon and a truncated protein.

Urinary calcium concentrations were low, despite adequate oralintake of calcium; therefore, the patient took daily supplements of500 mg of calcium. She also took two doses of 100,000 IU vitaminD every two weeks, then subsequently every 2 months. Bisphos-phonate was used to slow down osteoporosis, and involved yearlydoses of 5 mg of zoledronic acid. At one year, this treatment hadreduced the number of painful attacks from three or four per monthto only two per month, with a numeric pain rating reduced from 8


out of 10 to 6 out of 10. In addition, the concentrations of biologicalmarkers of bone resorption also declined: at 12 months CTX levelswere reduced from 391 to 100 pg/mL and osteocalcin levels werereduced from 18 to 8.1 ng/mL.



C. Deprouw et al. / Joint Bone Spine xxx (2015) xxx–xxx 3

Fig. 2. A. Radiographs of the hands showing resorption of the distal phalanges. B. Radiographs of the feet showing subchondral bone resorption of the fifth metatarsophalangeala ith pses

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nd proximal interphalangeal right foot joints, and a fracture due to osteoporosis whowing acro-osteolysis with bone loss on several fingers.

. Discussion

Here, we report a case of very rare disease, Hajdu-Cheney syn-rome, also known as acro-osteolysis dominant type (AOD). Tohe best of our knowledge, over 80 cases have been describedn the literature to date, most of them in recent genetic stud-es [1–4]. Hajdu-Cheney syndrome is a genetic disorder, whichnvolves de novo mutations in most cases, but also autosomal dom-nant inheritance in multiplex familial cases. Our patient did notave any children or siblings and there was no similar case in her

amily.There are no established criteria for this disease, although

t is characterized by the following clinical manifestations:cro-osteolysis, severe osteoporosis associated with additionalssification anomalies, hypermobility, and a craniofacial dys-orphic syndrome. Acro-osteolysis, is generally symmetric and

ilateral, and mostly painless although occasional inflammatoryare-ups lead to the shorting of digits (with pseudo-clubbing).steoporosis is severe and leads to numerous fractures with defor-


ations. Vertebrae are mostly affected with vertebral collapse,hich results in a short stature. Joint hypermobility is usuallyresent without mild skin hyperextensibility or tissue fragility withasy bruising, and subluxations or dislocations are not common

udarthrosis of the fifth left metatarsal. C. 3D surfacic CT images of the hands nicely

unlike in systemic disease of connective tissue (Ehlers-Danlos syn-drome hypermobility type, Marfan’s disease). Dysmorphia involvesthe loss of teeth, a dolichocephalic skull, a short neck, micrognathia,down-slanted palpepral fissures, hypertelorism, palpebral ptosis,thick eyebrows, long philtrum, flat and broad nasal base (the nos-trils may also be anteverted), low set and posteriorly rotated ears,coarse hair, thin upper lip, and downturned mouth. Our patient pre-sented down-slanted palpebral fissures, low set ears, broad nosewith anteverted nostrils, coarse hair and eyebrows.

Radiographs of patients with Hajdu-Cheney syndrome com-monly show acro-osteolysis (band resorption of the middle thirddistal phalanx), persistent cranial sutures, absent or hypoplas-tic frontal sinuses, an elongated sella turcica, basilar invaginationor platybasia, biconcave vertebrae, scoliosis and spondylolisthe-sis, wavy fibulas, coxa vara. Other clinical features may also bepresent including a cleft palate (present in our patient), kidneycysts, heart defects (coarctation of aorta, patent ductus arterio-sus, septal defect), chest deformity with respiratory failure andrecurrent respiratory tract infections, ventricular dilatation, basilar


compression, syringohydromyelic cavities, hearing loss, and abnor-mal deep voice. These malformations are rarely observed. In allcases of the literature, reported biological variables are within nor-mal ranges, including phosphocalcic variables.



4 C. Deprouw et al. / Joint Bone Spine xxx (2015) xxx–xxx

Fig. 3. A. Protein domains of NOTCH2. EGF: epithelial growth factor; NLR: cysteine-rich Lin12-NOTCH repeats; TMD: transmembrane domain; NLS: nuclear localisationd ic acim on of

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omain; ANK: ankyrin repeats; PEST: domain containing conserved proline-glutamutations. B. NOTCH2 gene: we identified Q2223X C > T mutation in the 34 (last) ex

The genetic bases of this syndrome were recently decipherednd NOTCH2 was identified as a causal gene. NOTCH2 proteinnhibits chondrogenesis and osteoblast differentiation and acti-ates osteoclast differentiation. The correct duration of the NOTCHignal is ensured by the proline (P), glutamic acid (E), serine (S),hreonine (T) rich (PEST) motif, which is located in the C termi-us of the receptor and is necessary for the degradation of NICDy the proteosome. Activating mutations in NOTCH2 stimulateOTCH2 signalling and promote bone loss. The mutation found inur patient (Q2223X C > T) has already been described by Majew-ki et al. [2]. Eighteen other mutations in NOTCH2 have also beendentified.

Despite this recent improvement in the knowledge of the dis-ase, no cure is available. Although very few studies have beenublished, some data suggest that bone mineral density can beemarkably improved by bisphosphonate treatment associatedith supplementation with calcium and vitamin D [5–8]. In our

ase, one year after 5 mg of zoledronic acid, pain in the distalxtremities was less severe and markers of bone disease hadeclined. There are no data available for RANKL inhibitors, whichay be another treatment option for this condition.


Acro-osteolysis is the hallmark of the Hajdu-Cheney syndromeut this finding is not uncommon and can be observed in severalonditions. Studies have attempted to classify acro-osteolysis asollows [9–12]:

d-serine-threonine-rich motifs. The arrow indicates the location of the truncating our patient by direct DNA sequencing of all 34 exons.

• familial: hereditary acro-osteolysis or Hajdu-Cheney, pycn-odysostosis, acro-osteopathia ulceromutilans familiaris, Roth-mud’s syndrome, osteogenesis imperfecta, Hutchinson-Gilfordprogeria syndrome;

• idiopathic or non-familial: one idiopathic form is called Bureau-Barrière syndrome, which mostly affects men (often alcoholics)and is associated with trophic ulcers, muscular atrophy and sec-ondary acro-osteolysis of the distal phalanges. Acquired formsare mainly associated with numerous skin, vascular and sys-temic diseases including Buerger’s disease, systemic sclerosis(SSc), dermatomyositis, Sjögren’s syndrome, sarcoidosis, diabeticgangrene, epidermolysis bullosa, hyperparathyroidism, reticu-lohistiocytosis, neurotrophic diseases, pachydermoperiostosis,porphyria, psoriatic and rheumatoid arthritis, renal osteodystro-phy and tumors;

• occupational: exposition to polyvinyl chloride (due to immuno-allergic vasculitis lesions), venom or phenytoin, mechanicalstress (guitar playing).

Acro-osteolysis clearly comprises a vascular component, whichhas been investigated in SSc with strong evidence to suggest that


acro-osteolysis is an ischaemic manifestation of SSc: Johnstoneet al. examined 101 patients with SSc and found that 76% of patientswith moderate/severe acro-osteolysis had severe digital ischaemiawhereas this clinical feature was present in only 29% of those with


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ormal/minimal digital acro-osteolysis [13]. Avouac et al. found aignificant association between the resorption of distal phalangesnd digital ulcers in 120 patients with SSc [14] and in another studynvolving 103 patients with SSc they reported that digital ulcersredict the progression of acro-osteolysis with a hazard ratio of 1215]. The mechanisms leading to acro-osteolysis in Hajdu-Cheneyyndrome remain unknown. Here, we performed an angio-MRI tovaluate the vascular component of acro-osteolysis in our patient;owever, the results tended to rule out small vessel injury.

Hajdu-Cheney syndrome is a very rare condition that rheuma-ologists may encounter in patients referred for acro-osteolysis,evere osteoporosis or dysmorphic syndrome. Although the geneticasis of this disease has been deciphered and NOTCH2 has been

dentified as a causal gene, there is still no cure and patients areurrently treated with bone anti-resorptive agents. Acro-osteolysiss usually observed in the context of systemic skin and vasculariseases such as disorders of connective tissue.

isclosure of interest

The authors declare that they have no conflicts of interest con-erning this article.


eferences

[1] Isidor B, Lindenbaum P, Pichon O, et al. Truncating mutations in the lastexon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet2011;43:306–8.

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PRESSpine xxx (2015) xxx–xxx 5

[2] Majewski J, Schwartzentruber JA, Caqueret A, et al. Mutations inNOTCH2 in families with Hajdu-Cheney syndrome. Hum Mutat 2011;32:1114–7.

[3] Simpson MA, Irving MD, Asilmaz E, et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet2011;43:303–5.

[4] Gu JM, Hu YQ, Zhang H, et al. A mutation in NOTCH2 gene in a Chinese patientwith Hajdu-Cheney syndrome. Joint Bone Spine 2013;80:548–9.

[5] Drake WM, Hiorns MP, Kendler DL. Hadju-Cheney syndrome: response totherapy with bisphosphonates in two patients. J Bone Miner Res 2003;18:131–3.

[6] Hwang S, Shin DY, Moon SH, et al. Effect of zoledronic acid on acro-osteolysisand osteoporosis in a patient with Hajdu-Cheney syndrome. Yonsei Med J2011;52:543–6.

[7] McKiernan FE. Integrated anti-remodeling and anabolic therapy for the osteo-porosis of Hajdu-Cheney syndrome. Osteoporos Int 2007;18:245–9.

[8] McKiernan FE. Integrated anti-remodeling and anabolic therapy for theosteoporosis of Hajdu-Cheney syndrome: 2-year follow-up. Osteoporos Int2008;19:379–80.

[9] Cunha I, Saavedra MJ, Oliveira MA, et al. Hajdu-Cheney syndrome: a case ofacroosteolysis. Acta Reumatol Port 2007;32:169–74.

10] Maroteaux P, Le Merrer M, editors. Maladies osseuses de l’enfant. France: Flam-marion; 2002.

11] O’Reilly MAR, Shaw DG. Hajdu-Cheney syndrome. Ann Rheum Dis1994;53:276–9.

12] Sahin A, Pepeler MS, Shimbori N. A patient with acro-osteolysis syndrome:Hajdu-Cheney. Intern Med 2010;49:87–8.

13] Johnstone EM, Hutchinson CE, Vail A, et al. Acro-osteolysis in systemic scle-rosis is associated with digital ischaemia and severe calcinosis. Rheumatology2012;51:2234–8.


14] Avouac J, Guerini H, Wipff J, et al. Radiological hand involvement in systemicsclerosis. Ann Rheum Dis 2006;65:1088–92.

15] Avouac J, Mogavero G, Guerina H, et al. Predictive factors of hand radio-graphic lesions in systemic sclerosis: a prospective study. Ann Rheum Dis2011;70:630–3.


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