88
Short case report
Hajdu–Cheney syndrome: phenotypical progression with de-novo NOTCH2 mutation Maria Descartesa,b,*, Kitiwan Rojnueangnita,*, Laura Colea, Amelia Suttona,c, Sarah L. Morgand, Lysanne Patrye and Mark E. Samuelse,f Clinical Dysmorphology 2014, 23:88–94 a
b
c
Departments of Genetics, Pediatrics, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, dDepartment of Medicine, and UAB Osteoporosis Prevention and Treatment Clinic, Division of Clinical Immunology and Rheumatology, the University of Alabama at Birmingham, Birmingham, Alabama, USA, eResearch Centre of Ste-Justine Hospital, Department of Medicine, University of Montreal and fDepartment of Medicine, University of Montreal, Montreal, Quebec, Canada
List of key features Acroosteolysis Short stature Coarse hair Coarse face Down-slanting palpebral fissures Thick eyebrows Simple and low-set ears Scoliosis
Introduction Hajdu–Cheney syndrome (HCS; MIM 102500) is a rare genetic skeletal syndrome with autosomal dominant inheritance. It is characterized by acroosteolysis of the distal phalanges, generalized osteoporosis, craniofacial and dental anomalies, and proportionate short stature. It was first described by Hajdu and Kauntze (1948) and Cheney (1965). Brennan and Pauli (2001) reviewed HCS and described 52 cases that met their inclusion criteria. The inclusion criteria included acroosteolysis plus at least three of seven findings: wormian bones or open sutures of the skull, platybasia, premature loss of teeth, micrognathia, coarse hair, midface flattening, and short stature. Other associated findings include hearing loss, renal cysts, basilar invagination, and cardiovascular anomalies (Ramos et al., 1998; Isidor et al., 2011; Simpson et al., 2011). At birth, there are no specific dysmorphic features, with only half of patients displaying micrognathia and/or hypoplastic mandibles (Brennan and Pauli, 2001). Although there are subtle manifestations of HCS in childhood, the phenotype becomes more evident in adolescence and adulthood. Growth typically starts to slow in early childhood. Acroosteolysis, the definitive characteristic of this disease, usually develops in late childhood or adolescence and is more severe in the hands than in the feet (Hajdu and Kauntze, 1948; Brennan and Pauli, 2001). Once bone *Maria Descartes and Kitiwan Rojnueangnit: co-first authors. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0962-8827
Correspondence to Maria Descartes, MD, Department of Genetics, University of Alabama at Birmingham, Kaul 210A 1720, 2nd AVE South, Birmingham, AL 35294-0024, USA Tel: + 1 205 934 4973; fax: + 1 205 975 6389; e-mail: [email protected] Received 12 November 2013 Accepted 4 February 2014
resorption begins, the progression is slow but inevitable. The acroosteolytic changes may be accompanied by sensory changes, such as burning pain, edema, and paresthesias. Generalized and local joint hypermobility is commonly reported at all ages. Spinal abnormalities, including instability, vertebral compression fractures, biconcave ‘fishbone’ deformities, lumbosacral spondylolisthesis, scoliosis, kyphosis, platybasia, and basilar invagination, become debilitating in late adolescent to adulthood. Reported neuromuscular complications include muscular weakness, hydrocephalus, stretching of the cranial nerves, increased intracranial pressure, foramen magnum compression, peripheral neuropathy, and visual loss as a result of platybasia and basilar invagination (Hajdu and Kauntze, 1948; Brennan and Pauli, 2001). Dental problems and premature dental loss are common in HCS (Brennan and Pauli, 2001). Life expectancy is considered to be normal. In 2011, several groups independently identified mutations in NOTCH2 in HCS (Isidor et al., 2011; Majewski et al., 2011; Simpson et al., 2011). These mutations are all heterozygous and cause protein truncations near the carboxyl terminus of the protein. These truncations may lead to protein stabilization through deletion of a C-terminal, proline–glutamate–serine–threonine-rich (PEST) domain. Heterozygous truncating mutations in the same area are also responsible for serpentine fibulapolycystic kidney syndrome. Both disorders share radiological and clinical features, including defective bone mineralization (Gray et al., 2012). There is much debate as to whether these disorders are the same or whether they represent two separate entities. In contrast, mutations elsewhere in the NOTCH2 gene lead have been found in some patients with Alagille syndrome, either in isolation or associated with mutations in JAG1 (Kamath et al., 2012). The Notch2 protein functions as a signal for regulation of bone homeostasis (Isidor et al., 2011), embryogenesis, and skeletogenesis (Loomes et al., 2002). A homozygous deletion in the NOTCH2 gene leads to embryonic death in mice (McCright et al., 2001). DOI: 10.1097/MCD.0000000000000034
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Hajdu–Cheney syndrome Descartes et al. 89
From birth until adolescence, there is considerable clinical information available describing the HCS phenotype. Beginning with early adulthood (20–33 years), the data become more sporadic. Here, we report a 47-year-old female with HCS and present detailed clinical data on disease progression throughout her life, including molecular genetics confirmation of the diagnosis.
Clinical report The patient was first seen in our genetics clinic at age 47 years because of her history of osteoporosis, scoliosis, and loss of height. Her weight was 60 kg (the 50th–75th centile), height was 149 cm (less than the fifth centile), and her head circumference was 57 cm (the 75th–90th centile). Her voice was low-pitched, and her hair was thick and coarse with low anterior and posterior hairlines. Her skull had a depression in the coronal region, and her facies was coarse. She had bilateral epicanthal folds, down-slanting palpebral fissures, thick eyebrows, a flat and broad nasal bridge, broad nose, malar hypoplasia, long and smooth philtrum, and relative prognathism. Her ears were simple and low-set. She had a full face with prominent ‘jowls’ and a short neck (Fig. 1f). The mouth was edentulous. Her back exam demonstrated thoracolumbar scoliosis. Her hands and feet were fleshy, and the digits were abnormally curved, broad, and short with soft tips.
There was marked hyperflexibility of the interphalangeal joints and brachytelenphalangy. The nails were thick and gray–yellow in color (Fig. 2). Acroosteolytic changes in hands were more severe than in the feet. Her skin was redundant and thicker in her hands, feet, face, and neck. The acroosteolytic regions had mildly decreased vibratory, light touch, and pin-prick sensation, and decreased sharp– dull discrimination. She also had mild bilateral conductive hearing loss at this age. She was the second child born to a 24-year-old, G3P1 white mother and a 31-year-old white father. The mother was 165 cm, the father was 183 cm. She was born at term by vaginal delivery after an uneventful gestation with a birth weight of 4 kg (90th centile) and length of 53 cm (90th centile). She was noted at birth to have coarse facies, synophrys, and a patent ductus arteriosus, which was ligated at the age of 4 years. During infancy and early childhood period, she had swallowing problems with aspiration of solids, and frequent upper respiratory infections, ear infections, and bronchitis. She had generalized joint hypermobility and complained of frequent pain in both hands and feet as a child. She had normal cognitive development except speech delay. She denied any learning disability.
Fig. 1
Facial features of the patient at 4 months (a) showed only synophrys, at 8 months (b), showed more dysmorphic features including hypotelorism, and epicanthal folds, at 20 months (c), 40 months (d), at 8 years (e), noted increasing coarse face, tubular nasal bridge and prominent eyebrows, in addition to synophrys with brachydactyly, and at 47 years (f) noted the coarse and full face, bilateral epicanthic folds, down-slanting palpebral fissures, thick eyebrows, a flat and broad nasal bridge, broad nose, malar hypoplasia, long and smooth philtrum, relative prognathism, and short neck.
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Fig. 2
The patient’s hands (a) showing bilateral fleshy of hands with abnormally curved, broad, and short tips of the digits and thick and gray–yellow colored nails. AP view of right hand (b) showing absence of the majority of middle and distal phalanges of all the fingers of both hands, and AP view of left foot (c) showing osteolysis of the distal phalanges. AP, anteroposterior.
She started wearing glasses for myopia as a teenager. She also noticed coarsening of her facial features, shortening of her fingers and toes, and thickening of her nails and hair. She began losing height at this time. Her maximum height was 155 cm (10th centile) in her 20s. As shown in Fig. 1a–f, her phenotype was progressive. She lost her teeth in her 30s because of receding gums, hypermobility, and instability. During that period, she started having constant burning pain of her feet, hands, and back with activity. At age 42, she was involved in a motor vehicle accident and fractured her C2 vertebra. After this car accident, she developed severe neck pain and worsening of the pain in her back and legs. She described the pain as constant, and it intensified with movement, walking, sitting, standing, and lying down for long periods of time. There was also numbness, tingling, burning pain, and edema of her hands and feet. She also complained of weakness, shortness of breath, and loss of balance. In addition, she developed urinary incontinence and constipation. Because of the pain and associated symptoms, the patient filed for disability. Neither spinal blocks with bracing nor spinal fusion surgery provided significant relief of the pain. Currently, a pain specialist follows the patient because of her chronic, debilitating pain. The diagnosis of scoliosis, osteoporosis, and degenerative disc disease was confirmed at age 45. The dual-energy X-ray absorptiometry (DEXA) scan showed a T-score of – 4.3 in the lumbar region, and a T-score of – 1.9 in the femur region. She had one healthy brother and four healthy children. There was no reported family history of short stature, intellectual disability and/or learning disabilities. Upon initial evaluation, her skeletal survey showed osteoporosis. The skull demonstrated nonfusion of the occipital sutures without wormian bones or focal lesions and mild basilar invagination (Fig. 3a). There was compression and chronic fractures of the second, third,
and seventh cervical vertebrae (Fig. 3b), severe cervico– thoraco–lumbar spinal scoliosis (Fig. 3c and d), evidence of multiple old compression deformities of the third and the fourth thoracic vertebrae and of the fifth lumbar vertebra (Fig. 3e). Her hand and foot radiographs showed the loss of middle and distal phalangeal bones (Fig. 2b and c). Her echocardiogram showed moderate tricuspid regurgitation. A renal ultrasound revealed small cysts on the mid portion of the left kidney. Because of her diagnosis of osteoporosis, after her spinal fusion, she was started on teriparatide, calcium, and vitamin D. The patient had a statistically significant increase in the bone mineral density after teriparatide therapy. Post-treatment the DEXA scan showed a T-score of – 3.0 in the lumbar region, and a T-score of – 1.3 in the femur region.
Molecular genetics testing The NOTCH2 gene, at C-terminal exon was sequenced by using standard PCR-based Sanger sequencing methodology. This revealed a novel heterozygous mutation, c.6933delT, a single base deletion that leads to a frameshift mutation, p.His2212Glnfs*9, predicted to delete the last 248 amino acids of the Notch2 protein, including the presumptive PEST domain (Fig. 4a and b). Neither her parents nor her children carried this mutation.
Discussion HCS is a rare progressive and debilitating genetic disorder that is characterized by a high degree of phenotypical pleiotropy. The features become more evident during adolescence and adulthood. This is not the first case report of adult classic HCS; however, it is the first case report that details the disease progression from childhood to adulthood as documented by photographic series. Previously, the diagnosis of HCS was based on the phenotype and radiographic findings. Currently, molecular genetic testing is used to confirm the diagnosis. Since 2011, fewer than 40 additional cases of
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Hajdu–Cheney syndrome Descartes et al. 91
Fig. 3
Lateral view of skull (a) showing nonfusion of occipital bone (short arrow), chronic fracture of C2 and C3 (long arrow), and mild basilar invagination. Lateral view of cervical spine (b) showing the posterior angulation of the dens with mild anterior widening of C2–C3 intervertebral disc space, and mild compression deformity of C7 vertebral body. AP view of thoracic (c) and lumbar spines (d) showing marked osteoporosis, and significant thoracolumbar scoliosis. Lateral view of lumbar spines (e) showing marked osteoporosis, and compression fracture of the fifth lumbar vertebra. AP, anteroposterior.
HCS have been reported with confirmed mutations in the NOTCH 2 gene (Isidor et al., 2011; Gu et al., 2013; Narumi et al., 2013; Stathopoulos et al., 2013; Zhao et al., 2013). All mutations were nonsense and frameshift mutations, predicted to result in a truncated protein, and were in the exon 34, leading to lack of the PEST domain. The mutation in our patient, a tyrosine deletion, was a de-novo mutation, but also causes a truncated protein without the PEST domain. The phenotypes of our patient were similar to other adults with HCS (Table 1) (Brennan and Pauli, 2001; Narumi et al., 2013; Stathopoulos et al., 2013). Her progressive musculoskeletal abnormalities are consistent with the major reported findings in HCS in adulthood. There have been reports of back pain and pain in hands and feet in other adults with HSC, but the severity has not been detailed in the literature. Her pain seemed more severe and aggressive than other reported cases as the pain was so debilitating that she filed for disability. Her other neurological findings, including headaches, poor balance, dizziness, decreased strength, and decreased sensitivity to temperature and pain are likely because of basilar invagination. Leidig-Bruckner et al. (1999) suggested that the osteoporosis in HCS is related to low peak bone mass and high
bone turnover, with insufficient bone formation to compensate for the increased bone resorption. Bisphosphonates have been reported as an effective therapy in HCS to inhibit osteoclastic activity (Galli-Tsinopoulou et al., 2012). However, this patient did not receive bisphosphonate therapy because her orthopedic surgeon preferred an anabolic therapy after her extensive surgical instrumentation. The DEXA scan preteriparatide and post-teriparatide treatment showed a significant improvement in the bone density. The T-score increased from – 4.3 to – 3.0 in the lumbar region and also increased from – 1.9 to – 1.3 in the femur region. The presence of the mutant Notch2 protein, with continuous osteoclastic stimulation, is the likely explanation for osteoporosis in these patients. In the future, it is possible that Notch inhibitors may impede the evolution of bone loss (Simpson et al., 2011) and improve the treatment of osteoporosis in these patients.
Conclusion
HCS should be considered in the differential diagnosis of individuals who present with short stature, low bone mass, and acroosteolysis. The clinical diagnosis can be confirmed with molecular analysis of the NOTCH2 gene. As described in this case report, the natural history of HCS is characterized by coarsening of the facial features,
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92 Clinical Dysmorphology 2014, Vol 23 No 3
Fig. 4
(a)
A
6915 A A
T
G C
6920 A G C
C
T
6925 T T
G
G C
6930 A C
A
T
G
6935 G G
G C
C
6940 A G
C
A
6945 C T G
T
G C
6950 T T
C
*032.scf
A
A
A
T
G C
A
G C
C
T
T
T
G
G C
A
C
A
T
G
G G
G C
C
A
G
C
A
C T
T
G C
T
T
C
*-2F.ab1
A
A
A
T
G C
A
G C
C
T
T
T
G
G C
A
C
A
G
G G
A A
N N N N T G C A ∗ ∗∗ ∗ ∗∗
A N G C ∗ ∗
C C
T T
T T
N N T G ∗ ∗∗
G N G C ∗
N A ∗
N N C A ∗ ∗∗
N ∗ A A
N ∗ G G
N ∗ C C
N ∗ A A
T ∗ C C
N ∗ G G
C
A A
N ∗ C C
T
N A ∗∗
N C ∗ G G G C G G G C
T
*-2R.ab1 *032.scf
N ∗ N T ∗
T T
T T
C C
*408.gbk *-2F.ab1
E E
2210 L L
A A
345 T T
C
T
205 C
M M
Q Q
P P
R--> NM_024408_F_Synthesis_7032.scf --> Quality(0–100):83 5000 310 315 320 4000 A A A T G C A G C C T T T G G 3000 2000 1000 0 S--> Deb2_Notch2×34-2F.ab1--> Quality(0–100):0 1500 170 175 180 1000 A A A T G C A G C C T T T G G 500 0 2000 1500 1000 500 0 3100 3200 3150 2000 1500 1000 500 0 S C c.6428T > C c.6449_6450delCT c.7119T > G p.His2212Glnfs*9 p.Pro2071 p.Leu p.Leu p.Pro p.Tyr Asnfs*4 2148* 2148* 2149Arg 2373* fs*2 De novo De novo De novo Familial De novo Familial
Our patient
Narumi et al. (2013)
Comparison characteristics of our patient with NOTCH2 mutations
Sex Age Nucleotide Protein
Table 1
30
79 38
95 59
79
68 32 24 52
62 85 88 71
94 83
86
9 25 NA
60 49
67 53
84
33 12 18 51
32 56 28 67
37 21
64
34 NOTCH2 Brennan and mutation (%)a Pauli (2001) (%)
Hajdu–Cheney syndrome Descartes et al. 93
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Clinical Dysmorphology 2014, Vol 23 No 3
progressive acroosteolysis, and osteoporosis. Treatment is aimed at improving mobility and increasing bone mass and includes a combination of medical and surgical therapy.
Acknowledgements Conflicts of interest
Leidig-Bruckner G, Pfeilschifter J, Penning N, Limberg B, Priemel M, Delling G, Ziegler R (1999). Severe osteoporosis in familial Hajdu–Cheney syndrome: progression of acro-osteolysis and osteoporosis during long-term follow-up. J Bone Miner Res 14:2036–2041. Loomes KM, Taichman DB, Glover CL, Williams PT, Markowitz JE, Piccoli DA, et al. (2002). Characterization of Notch receptor expression in the developing mammalian heart and liver. Am J Med Genet 112:181–189. Majewski J, Schwartzentruber JA, Caqueret A, Patry L, Marcadier J, Fryns JP, et al.
There are no conflicts of interest.
(2011). Mutations in NOTCH2 in families with Hajdu–Cheney syndrome. Hum Mutat 32:1114–1117. McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, et al. (2001). Defects in
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development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development 128:491–502. Narumi Y, Min BJ, Shimizu K, Kazukawa I, Sameshima K, Nakamura K, et al.
Brennan AM, Pauli RM (2001). Hajdu–Cheney syndrome: evolution of phenotype and clinical problems. Am J Med Genet 100:292–310. Cheney WD (1965). Acro-osteolysis. Am J Roentgenol Radium Ther Nucl Med 94:595–607. Galli-Tsinopoulou A, Kyrgios I, Giza S, Giannopoulou EM, Maggana I, Laliotis N (2012). Two-year cyclic infusion of pamidronate improves bone mass density and eliminates risk of fractures in a girl with osteoporosis due to Hajdu–Cheney syndrome. Minerva Endocrinol 37:283–289. Gray MJ, Kim CA, Bertola DR, Arantes PR, Stewart H, Simpson MA, et al. (2012). Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu–Cheney syndrome. Eur J Hum Genet 20:122–124. Gu JM, Hu YQ, Zhang H, Wang C, Hu WW, Yue H, et al. (2013). A mutation in NOTCH2 gene in a Chinese patient with Hajdu–Cheney syndrome. Joint Bone Spine 80:548–549. Hajdu N, Kauntze R (1948). Cranio-skeletal dysplasia. Br J Radiol 21:42–48. Isidor B, Lindenbaum P, Pichon O, Bezieau S, Dina C, Jacquemont S, et al. (2011). Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet 43:306–308. Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, et al. (2012). NOTCH2 mutations in Alagille syndrome. J Med Genet 49:138–144.
(2013). Clinical consequences in truncating mutations in exon 34 of NOTCH2: report of six patients with Hajdu–Cheney syndrome and a patient with serpentine fibula polycystic kidney syndrome. Am J Med Genet A 161:518–526. Ramos FJ, Kaplan BS, Bellah RD, Zackai EH, Kaplan P (1998). Further evidence that the Hajdu–Cheney syndrome and the ‘serpentine fibula-polycystic kidney syndrome’ are a single entity. Am J Med Genet 78:474–481. Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D, Elmslie FV, et al. (2011). Mutations in NOTCH2 cause Hajdu–Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet 43:303–305. Stathopoulos IP, Trovas G, Lampropoulou-Adamidou K, Koromila T, Kollia P, Papaioannou NA, Lyritis G (2013). Severe osteoporosis and mutation in NOTCH2 gene in a woman with Hajdu–Cheney syndrome. Bone 52: 366–371. Zhao W, Petit E, Gafni RI, Collins MT, Robey PG, Seton M, et al. (2013). Mutations in NOTCH2 in patients with Hajdu–Cheney syndrome. Osteoporos Int 24:2275–2281.
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Short case report
Hajdu–Cheney syndrome: phenotypical progression with de-novo NOTCH2 mutation Maria Descartesa,b,*, Kitiwan Rojnueangnita,*, Laura Colea, Amelia Suttona,c, Sarah L. Morgand, Lysanne Patrye and Mark E. Samuelse,f Clinical Dysmorphology 2014, 23:88–94 a
b
c
Departments of Genetics, Pediatrics, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, dDepartment of Medicine, and UAB Osteoporosis Prevention and Treatment Clinic, Division of Clinical Immunology and Rheumatology, the University of Alabama at Birmingham, Birmingham, Alabama, USA, eResearch Centre of Ste-Justine Hospital, Department of Medicine, University of Montreal and fDepartment of Medicine, University of Montreal, Montreal, Quebec, Canada
List of key features Acroosteolysis Short stature Coarse hair Coarse face Down-slanting palpebral fissures Thick eyebrows Simple and low-set ears Scoliosis
Introduction Hajdu–Cheney syndrome (HCS; MIM 102500) is a rare genetic skeletal syndrome with autosomal dominant inheritance. It is characterized by acroosteolysis of the distal phalanges, generalized osteoporosis, craniofacial and dental anomalies, and proportionate short stature. It was first described by Hajdu and Kauntze (1948) and Cheney (1965). Brennan and Pauli (2001) reviewed HCS and described 52 cases that met their inclusion criteria. The inclusion criteria included acroosteolysis plus at least three of seven findings: wormian bones or open sutures of the skull, platybasia, premature loss of teeth, micrognathia, coarse hair, midface flattening, and short stature. Other associated findings include hearing loss, renal cysts, basilar invagination, and cardiovascular anomalies (Ramos et al., 1998; Isidor et al., 2011; Simpson et al., 2011). At birth, there are no specific dysmorphic features, with only half of patients displaying micrognathia and/or hypoplastic mandibles (Brennan and Pauli, 2001). Although there are subtle manifestations of HCS in childhood, the phenotype becomes more evident in adolescence and adulthood. Growth typically starts to slow in early childhood. Acroosteolysis, the definitive characteristic of this disease, usually develops in late childhood or adolescence and is more severe in the hands than in the feet (Hajdu and Kauntze, 1948; Brennan and Pauli, 2001). Once bone *Maria Descartes and Kitiwan Rojnueangnit: co-first authors. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0962-8827
Correspondence to Maria Descartes, MD, Department of Genetics, University of Alabama at Birmingham, Kaul 210A 1720, 2nd AVE South, Birmingham, AL 35294-0024, USA Tel: + 1 205 934 4973; fax: + 1 205 975 6389; e-mail: [email protected] Received 12 November 2013 Accepted 4 February 2014
resorption begins, the progression is slow but inevitable. The acroosteolytic changes may be accompanied by sensory changes, such as burning pain, edema, and paresthesias. Generalized and local joint hypermobility is commonly reported at all ages. Spinal abnormalities, including instability, vertebral compression fractures, biconcave ‘fishbone’ deformities, lumbosacral spondylolisthesis, scoliosis, kyphosis, platybasia, and basilar invagination, become debilitating in late adolescent to adulthood. Reported neuromuscular complications include muscular weakness, hydrocephalus, stretching of the cranial nerves, increased intracranial pressure, foramen magnum compression, peripheral neuropathy, and visual loss as a result of platybasia and basilar invagination (Hajdu and Kauntze, 1948; Brennan and Pauli, 2001). Dental problems and premature dental loss are common in HCS (Brennan and Pauli, 2001). Life expectancy is considered to be normal. In 2011, several groups independently identified mutations in NOTCH2 in HCS (Isidor et al., 2011; Majewski et al., 2011; Simpson et al., 2011). These mutations are all heterozygous and cause protein truncations near the carboxyl terminus of the protein. These truncations may lead to protein stabilization through deletion of a C-terminal, proline–glutamate–serine–threonine-rich (PEST) domain. Heterozygous truncating mutations in the same area are also responsible for serpentine fibulapolycystic kidney syndrome. Both disorders share radiological and clinical features, including defective bone mineralization (Gray et al., 2012). There is much debate as to whether these disorders are the same or whether they represent two separate entities. In contrast, mutations elsewhere in the NOTCH2 gene lead have been found in some patients with Alagille syndrome, either in isolation or associated with mutations in JAG1 (Kamath et al., 2012). The Notch2 protein functions as a signal for regulation of bone homeostasis (Isidor et al., 2011), embryogenesis, and skeletogenesis (Loomes et al., 2002). A homozygous deletion in the NOTCH2 gene leads to embryonic death in mice (McCright et al., 2001). DOI: 10.1097/MCD.0000000000000034
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Hajdu–Cheney syndrome Descartes et al. 89
From birth until adolescence, there is considerable clinical information available describing the HCS phenotype. Beginning with early adulthood (20–33 years), the data become more sporadic. Here, we report a 47-year-old female with HCS and present detailed clinical data on disease progression throughout her life, including molecular genetics confirmation of the diagnosis.
Clinical report The patient was first seen in our genetics clinic at age 47 years because of her history of osteoporosis, scoliosis, and loss of height. Her weight was 60 kg (the 50th–75th centile), height was 149 cm (less than the fifth centile), and her head circumference was 57 cm (the 75th–90th centile). Her voice was low-pitched, and her hair was thick and coarse with low anterior and posterior hairlines. Her skull had a depression in the coronal region, and her facies was coarse. She had bilateral epicanthal folds, down-slanting palpebral fissures, thick eyebrows, a flat and broad nasal bridge, broad nose, malar hypoplasia, long and smooth philtrum, and relative prognathism. Her ears were simple and low-set. She had a full face with prominent ‘jowls’ and a short neck (Fig. 1f). The mouth was edentulous. Her back exam demonstrated thoracolumbar scoliosis. Her hands and feet were fleshy, and the digits were abnormally curved, broad, and short with soft tips.
There was marked hyperflexibility of the interphalangeal joints and brachytelenphalangy. The nails were thick and gray–yellow in color (Fig. 2). Acroosteolytic changes in hands were more severe than in the feet. Her skin was redundant and thicker in her hands, feet, face, and neck. The acroosteolytic regions had mildly decreased vibratory, light touch, and pin-prick sensation, and decreased sharp– dull discrimination. She also had mild bilateral conductive hearing loss at this age. She was the second child born to a 24-year-old, G3P1 white mother and a 31-year-old white father. The mother was 165 cm, the father was 183 cm. She was born at term by vaginal delivery after an uneventful gestation with a birth weight of 4 kg (90th centile) and length of 53 cm (90th centile). She was noted at birth to have coarse facies, synophrys, and a patent ductus arteriosus, which was ligated at the age of 4 years. During infancy and early childhood period, she had swallowing problems with aspiration of solids, and frequent upper respiratory infections, ear infections, and bronchitis. She had generalized joint hypermobility and complained of frequent pain in both hands and feet as a child. She had normal cognitive development except speech delay. She denied any learning disability.
Fig. 1
Facial features of the patient at 4 months (a) showed only synophrys, at 8 months (b), showed more dysmorphic features including hypotelorism, and epicanthal folds, at 20 months (c), 40 months (d), at 8 years (e), noted increasing coarse face, tubular nasal bridge and prominent eyebrows, in addition to synophrys with brachydactyly, and at 47 years (f) noted the coarse and full face, bilateral epicanthic folds, down-slanting palpebral fissures, thick eyebrows, a flat and broad nasal bridge, broad nose, malar hypoplasia, long and smooth philtrum, relative prognathism, and short neck.
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Fig. 2
The patient’s hands (a) showing bilateral fleshy of hands with abnormally curved, broad, and short tips of the digits and thick and gray–yellow colored nails. AP view of right hand (b) showing absence of the majority of middle and distal phalanges of all the fingers of both hands, and AP view of left foot (c) showing osteolysis of the distal phalanges. AP, anteroposterior.
She started wearing glasses for myopia as a teenager. She also noticed coarsening of her facial features, shortening of her fingers and toes, and thickening of her nails and hair. She began losing height at this time. Her maximum height was 155 cm (10th centile) in her 20s. As shown in Fig. 1a–f, her phenotype was progressive. She lost her teeth in her 30s because of receding gums, hypermobility, and instability. During that period, she started having constant burning pain of her feet, hands, and back with activity. At age 42, she was involved in a motor vehicle accident and fractured her C2 vertebra. After this car accident, she developed severe neck pain and worsening of the pain in her back and legs. She described the pain as constant, and it intensified with movement, walking, sitting, standing, and lying down for long periods of time. There was also numbness, tingling, burning pain, and edema of her hands and feet. She also complained of weakness, shortness of breath, and loss of balance. In addition, she developed urinary incontinence and constipation. Because of the pain and associated symptoms, the patient filed for disability. Neither spinal blocks with bracing nor spinal fusion surgery provided significant relief of the pain. Currently, a pain specialist follows the patient because of her chronic, debilitating pain. The diagnosis of scoliosis, osteoporosis, and degenerative disc disease was confirmed at age 45. The dual-energy X-ray absorptiometry (DEXA) scan showed a T-score of – 4.3 in the lumbar region, and a T-score of – 1.9 in the femur region. She had one healthy brother and four healthy children. There was no reported family history of short stature, intellectual disability and/or learning disabilities. Upon initial evaluation, her skeletal survey showed osteoporosis. The skull demonstrated nonfusion of the occipital sutures without wormian bones or focal lesions and mild basilar invagination (Fig. 3a). There was compression and chronic fractures of the second, third,
and seventh cervical vertebrae (Fig. 3b), severe cervico– thoraco–lumbar spinal scoliosis (Fig. 3c and d), evidence of multiple old compression deformities of the third and the fourth thoracic vertebrae and of the fifth lumbar vertebra (Fig. 3e). Her hand and foot radiographs showed the loss of middle and distal phalangeal bones (Fig. 2b and c). Her echocardiogram showed moderate tricuspid regurgitation. A renal ultrasound revealed small cysts on the mid portion of the left kidney. Because of her diagnosis of osteoporosis, after her spinal fusion, she was started on teriparatide, calcium, and vitamin D. The patient had a statistically significant increase in the bone mineral density after teriparatide therapy. Post-treatment the DEXA scan showed a T-score of – 3.0 in the lumbar region, and a T-score of – 1.3 in the femur region.
Molecular genetics testing The NOTCH2 gene, at C-terminal exon was sequenced by using standard PCR-based Sanger sequencing methodology. This revealed a novel heterozygous mutation, c.6933delT, a single base deletion that leads to a frameshift mutation, p.His2212Glnfs*9, predicted to delete the last 248 amino acids of the Notch2 protein, including the presumptive PEST domain (Fig. 4a and b). Neither her parents nor her children carried this mutation.
Discussion HCS is a rare progressive and debilitating genetic disorder that is characterized by a high degree of phenotypical pleiotropy. The features become more evident during adolescence and adulthood. This is not the first case report of adult classic HCS; however, it is the first case report that details the disease progression from childhood to adulthood as documented by photographic series. Previously, the diagnosis of HCS was based on the phenotype and radiographic findings. Currently, molecular genetic testing is used to confirm the diagnosis. Since 2011, fewer than 40 additional cases of
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Hajdu–Cheney syndrome Descartes et al. 91
Fig. 3
Lateral view of skull (a) showing nonfusion of occipital bone (short arrow), chronic fracture of C2 and C3 (long arrow), and mild basilar invagination. Lateral view of cervical spine (b) showing the posterior angulation of the dens with mild anterior widening of C2–C3 intervertebral disc space, and mild compression deformity of C7 vertebral body. AP view of thoracic (c) and lumbar spines (d) showing marked osteoporosis, and significant thoracolumbar scoliosis. Lateral view of lumbar spines (e) showing marked osteoporosis, and compression fracture of the fifth lumbar vertebra. AP, anteroposterior.
HCS have been reported with confirmed mutations in the NOTCH 2 gene (Isidor et al., 2011; Gu et al., 2013; Narumi et al., 2013; Stathopoulos et al., 2013; Zhao et al., 2013). All mutations were nonsense and frameshift mutations, predicted to result in a truncated protein, and were in the exon 34, leading to lack of the PEST domain. The mutation in our patient, a tyrosine deletion, was a de-novo mutation, but also causes a truncated protein without the PEST domain. The phenotypes of our patient were similar to other adults with HCS (Table 1) (Brennan and Pauli, 2001; Narumi et al., 2013; Stathopoulos et al., 2013). Her progressive musculoskeletal abnormalities are consistent with the major reported findings in HCS in adulthood. There have been reports of back pain and pain in hands and feet in other adults with HSC, but the severity has not been detailed in the literature. Her pain seemed more severe and aggressive than other reported cases as the pain was so debilitating that she filed for disability. Her other neurological findings, including headaches, poor balance, dizziness, decreased strength, and decreased sensitivity to temperature and pain are likely because of basilar invagination. Leidig-Bruckner et al. (1999) suggested that the osteoporosis in HCS is related to low peak bone mass and high
bone turnover, with insufficient bone formation to compensate for the increased bone resorption. Bisphosphonates have been reported as an effective therapy in HCS to inhibit osteoclastic activity (Galli-Tsinopoulou et al., 2012). However, this patient did not receive bisphosphonate therapy because her orthopedic surgeon preferred an anabolic therapy after her extensive surgical instrumentation. The DEXA scan preteriparatide and post-teriparatide treatment showed a significant improvement in the bone density. The T-score increased from – 4.3 to – 3.0 in the lumbar region and also increased from – 1.9 to – 1.3 in the femur region. The presence of the mutant Notch2 protein, with continuous osteoclastic stimulation, is the likely explanation for osteoporosis in these patients. In the future, it is possible that Notch inhibitors may impede the evolution of bone loss (Simpson et al., 2011) and improve the treatment of osteoporosis in these patients.
Conclusion
HCS should be considered in the differential diagnosis of individuals who present with short stature, low bone mass, and acroosteolysis. The clinical diagnosis can be confirmed with molecular analysis of the NOTCH2 gene. As described in this case report, the natural history of HCS is characterized by coarsening of the facial features,
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92 Clinical Dysmorphology 2014, Vol 23 No 3
Fig. 4
(a)
A
6915 A A
T
G C
6920 A G C
C
T
6925 T T
G
G C
6930 A C
A
T
G
6935 G G
G C
C
6940 A G
C
A
6945 C T G
T
G C
6950 T T
C
*032.scf
A
A
A
T
G C
A
G C
C
T
T
T
G
G C
A
C
A
T
G
G G
G C
C
A
G
C
A
C T
T
G C
T
T
C
*-2F.ab1
A
A
A
T
G C
A
G C
C
T
T
T
G
G C
A
C
A
G
G G
A A
N N N N T G C A ∗ ∗∗ ∗ ∗∗
A N G C ∗ ∗
C C
T T
T T
N N T G ∗ ∗∗
G N G C ∗
N A ∗
N N C A ∗ ∗∗
N ∗ A A
N ∗ G G
N ∗ C C
N ∗ A A
T ∗ C C
N ∗ G G
C
A A
N ∗ C C
T
N A ∗∗
N C ∗ G G G C G G G C
T
*-2R.ab1 *032.scf
N ∗ N T ∗
T T
T T
C C
*408.gbk *-2F.ab1
E E
2210 L L
A A
345 T T
C
T
205 C
M M
Q Q
P P
R--> NM_024408_F_Synthesis_7032.scf --> Quality(0–100):83 5000 310 315 320 4000 A A A T G C A G C C T T T G G 3000 2000 1000 0 S--> Deb2_Notch2×34-2F.ab1--> Quality(0–100):0 1500 170 175 180 1000 A A A T G C A G C C T T T G G 500 0 2000 1500 1000 500 0 3100 3200 3150 2000 1500 1000 500 0 S C c.6428T > C c.6449_6450delCT c.7119T > G p.His2212Glnfs*9 p.Pro2071 p.Leu p.Leu p.Pro p.Tyr Asnfs*4 2148* 2148* 2149Arg 2373* fs*2 De novo De novo De novo Familial De novo Familial
Our patient
Narumi et al. (2013)
Comparison characteristics of our patient with NOTCH2 mutations
Sex Age Nucleotide Protein
Table 1
30
79 38
95 59
79
68 32 24 52
62 85 88 71
94 83
86
9 25 NA
60 49
67 53
84
33 12 18 51
32 56 28 67
37 21
64
34 NOTCH2 Brennan and mutation (%)a Pauli (2001) (%)
Hajdu–Cheney syndrome Descartes et al. 93
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94
Clinical Dysmorphology 2014, Vol 23 No 3
progressive acroosteolysis, and osteoporosis. Treatment is aimed at improving mobility and increasing bone mass and includes a combination of medical and surgical therapy.
Acknowledgements Conflicts of interest
Leidig-Bruckner G, Pfeilschifter J, Penning N, Limberg B, Priemel M, Delling G, Ziegler R (1999). Severe osteoporosis in familial Hajdu–Cheney syndrome: progression of acro-osteolysis and osteoporosis during long-term follow-up. J Bone Miner Res 14:2036–2041. Loomes KM, Taichman DB, Glover CL, Williams PT, Markowitz JE, Piccoli DA, et al. (2002). Characterization of Notch receptor expression in the developing mammalian heart and liver. Am J Med Genet 112:181–189. Majewski J, Schwartzentruber JA, Caqueret A, Patry L, Marcadier J, Fryns JP, et al.
There are no conflicts of interest.
(2011). Mutations in NOTCH2 in families with Hajdu–Cheney syndrome. Hum Mutat 32:1114–1117. McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, et al. (2001). Defects in
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