Exploratory use of romosozumab for osteoporosis in a patient with Hajdu-Cheney syndrome: a case report.

Hajdu-Cheney syndrome (HCS) is an inherited skeletal disorder caused by mutations in the Notch homolog protein 2 gene (NOTCH2). Treatment of this rare disease is challenging because there are no established guidelines worldwide. Previous case reports using bisphosphonates, denosumab, or teriparatide suggested that curative treatment for HCS did not exist yet in terms of preventing the disease progression. Therefore, the efficacy of romosozumab for osteoporosis in patients with HCS needs to be evaluated. Herein, we report the case of a 43-year-old woman who had progressive acro-osteolysis and repeated fractures since the age of 29 years. Next-generation sequencing confirmed HCS with a mutation at nucleotide 6758G>A, leading to Trp2253Ter replacement in NOTCH2. Romosozumab treatment was initiated because she had already received bisphosphonate for more than 10 years at other hospitals. After 1 year of romosozumab treatment, the bone mineral density (BMD) increased by 10.2%, 6.3%, and 1.3%, with Z scores of -2.9, -1.6, and -1.2 at the lumbar spine, femoral neck, and total hip, respectively. In addition, C-telopeptide was suppressed by 26.4% (0.121 to 0.089 ng/mL), and procollagen type I N-terminal propeptide increased by 18.7% (25.2 to 29.9 ng/mL). This was the first report of romosozumab treatment in patient with osteoporosis and HCS in Korea. One year of romosozumab treatment provided substantial gains in BMD with maintaining the last acro-osteolytic status without deteriorating, representing a possible treatment option for HCS.

Distinct severity of phenotype in Hajdu-Cheney syndrome: a case report and literature review.

BACKGROUND: Hajdu-Cheney syndrome (HCS) is a rare inherited skeletal disorder caused by pathogenic mutations in exon 34 of NOTCH2. Its highly variable phenotypes make early diagnosis challenging. In this paper, we report a case of early-onset HCS with severe phenotypic manifestations but delayed diagnosis. CASE PRESENTATION: The patient was born to non-consanguineous, healthy parents of Chinese origin. She presented facial anomalies, micrognathia and skull malformations at birth, and was found hearing impairment, congenital heart disease and developmental delay during her first year of life. Her first visit to our center was at 1 year of age due to cardiovascular repair surgery for patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Skull X-ray showed wormian bones. She returned at 7 years old after she developed progressive skeletal anomalies with fractures. She presented with multiple wormian bones, acro-osteolysis, severe osteoporosis, bowed fibulae and a renal cyst. Positive genetic test of a de novo heterozygous frameshift mutation in exon 34 of NOTCH2 (c.6426dupT) supported the clinical diagnosis of HCS. CONCLUSION: This is the second reported HCS case caused by the mutation c.6426dupT in NOTCH2, but presenting much earlier and severer clinical expression. Physicians should be aware of variable phenotypes so that early diagnosis and management may be achieved.

Dental implications in Hajdu-Cheney syndrome: A novel case report and review of the literature.

OBJECTIVE: To identify the molecular genetic etiology of an individual with a dysmorphic face, unusual teeth mobility, and root resorption. SUBJECTS AND METHODS: DNA samples were collected from a trio of family members, and whole-exome sequencing was performed. RESULTS: Mutational analysis revealed a de novo mutation (c.6787C>T) in the last exon of the NOTCH2 gene. This mutation would introduce a premature stop codon [p.(Gln2263*)] and generate a truncated protein without C-terminus, escaping from the nonsense-mediated decay system. Sanger sequencing confirmed that this mutation was generated spontaneously. CONCLUSIONS: In this study, we identified a novel nonsense mutation in the last exon of the NOTCH2 gene causing Hajdu-Cheney syndrome. We described the genotype and phenotype correlation and the related dental complications. These results will advance the understanding of the NOTCH2 signaling in periodontitis and root resorption.

Extreme proximal junctional kyphosis-a complication of delayed lambdoid suture closure in Hajdu-Cheney syndrome: a case report and literature review.

PURPOSE: To describe the manifestations, surgical treatment, and potential complications of Hajdu-Cheney syndrome (HCS), and the management of these complications. METHODS: The clinical presentation, management and outcome of HCS with severe osteoporosis and open skull sutures is presented, together with a literature review. RESULTS: A 20-year-old female with HCS underwent posterior occipitocervical fusion for symptoms of progressive basilar invagination. Because of delayed lambdoid suture closure, the stiff fusion construct lead to increased suture distraction, most notably in the upright (suture-open) position, with relief in the supine (suture-closed) position. This was successfully remedied with extension of the fusion construct anteriorly over the skull vertex to the frontal bones. CONCLUSIONS: In patients with HCS and other conditions with delayed suture closure, the surgeon must be cognizant of the presence of mobility at the suture lines, and consider extending the fusion construct anteriorly over the skull vertex up to the frontal bones. Because of significant osteoporosis in these syndromes, multiple fixation points and augmentation with bone graft are important principles.

The Age Dependent Progression of Hajdu-Cheney Syndrome in Two Families.

Hajdu-Cheney syndrome (HCS) is a rare multi-system disease with autosomal dominant inheritance and skeletal involvement, resulting mostly in craniofacial dysmorphy with mid-face hypoplasia, dental anomalies, short stature, scoliosis, shortening of the digits and nail beds, acro-osteolysis and osteoporosis. We report the progression of clinical and radiographic findings in five patients with Hajdu-Cheney syndrome from two families. A custom capture array designed to capture exons and adjacent intron sequences of 230 selected genes were used for molecular analyses, and the pathogenic variants identified were confirmed by PCR and Sanger sequencing. In both families we observed age-dependent changes in the disease, with a progression of pain in older patients, a shortening of digits and nail beds on both the hands and feet, kyphoscoliosis and the persistence of Wormian bones in lambdoid sutures. Molecular analyses performed in two patients revealed that they are heterozygotes for a c.6255T>A (p.Cys2085*) variant in the NOTCH2 gene, resulting in a premature stop-codon. Bone mineral density (Z-score < -2) did not improved in a girl treated with calcium and vitamin D supplementation during childhood and bisphosphonate during adolescence. Hajdu-Cheney syndrome is a slowly progressive disease with a frequently unfavourable prognosis in elderly patients, especially for the development of dental anomalies, osteoporosis and the progression of skeletal complications requiring orthopedic surgeries.

Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations.

Notch plays an important function in skeletal homeostasis, osteoblastogenesis, and osteoclastogenesis. Hajdu-Cheney syndrome (HCS) is a rare disease associated with mutations in NOTCH2 leading to the translation of a truncated NOTCH2 stable protein. As a consequence, a gain-of-NOTCH2 function is manifested. HCS is inherited as an autosomal dominant disease although sporadic cases exist. HCS is characterized by craniofacial developmental defects, including platybasia and wormian bones, osteoporosis with fractures, and acro-osteolysis. Subjects may suffer severe neurological complications, and HCS presents with cardiovascular defects and polycystic kidneys. An experimental mouse model harboring a HCSNotch2 mutation exhibits osteopenia secondary to enhanced bone resorption suggesting this as a possible mechanism for the skeletal disease. If the same mechanisms were operational in humans, anti-resorptive therapy could correct the bone loss, but not necessarily the acro-osteolysis. In conclusion, HCS is a devastating disease associated with a gain-of-NOTCH2 function resulting in diverse clinical manifestations.

Orofacial characteristics in a child with Hajdu-Cheney syndrome.

Hajdu-Cheney syndrome (HCS) also known as Cranio-skeletal dysplasia is a rare genetic disorder of bone metabolism. It is mainly characterized by acro-osteolysis and generalized osteoporosis. The other distinctive features include a dysmorphic face, short stature, aplasia of facial sinuses, and persistent cranial sutures. Although the condition begins to manifest since birth, the characteristic features become more prominent with age. This syndrome is usually recognized by dentists due to these craniofacial abnormalities. This case report aims to highlight a case of 6-year-old girl HCS who presented with aberrant facial features, premature exfoliation of teeth, unusual mobility of teeth and atypical root resorption in primary dentition.

An unusual presentation of diabetic ketoacidosis in familial hajdu-cheney syndrome: a case report.

A 21-year-old man with diabetic ketoacidosis (DKA) displayed short and clubbed fingers and marked eyebrow, which are typical of Hajdu-Cheney Syndrome (HCS). Laboratory findings confirmed type 1 diabetes mellitus (DM). After conservative care with hydration and insulin supply, metabolic impairment was improved. Examinations of bone and metabolism revealed osteoporosis and craniofacial abnormalities. The mutation (c.6443T>G) of the NOTCH2 gene was found. The patient was diagnosed with HCS and DM. There may be a relationship between HCS and DM, with development of pancreatic symptoms related to the NOTCH2 gene mutation.

A girl with Hajdu-Cheney syndrome and premature ovarian failure.

Hajdu-Cheney syndrome is an autosomal dominant disorder characterized by acroosteolysis of the distal phalanges associated with digit abnormalities, distinctive craniofacial changes, dental anomalies, and a proportionate short stature. The pubertal development of children with Hajdu-Cheney syndrome is usually normal in the literature, although we here first describe a girl who was found to have Hajdu-Cheney syndrome accompanied with premature ovarian failure. She showed a follicle-stimulating hormone-dominant response on luteinizing hormone-releasing hormone test and did not show any sex differentiation abnormality or adrenal steroid hormone deficiency. On the basis of the findings in our patient, premature ovarian failure may be a complication of Hajdu-Cheney syndrome and thus an early endocrinological evaluation of patients is important.

Hajdu-Cheney syndrome with severe dural ectasia.

Hajdu-Cheney syndrome (HCS) is an autosomal dominant condition comprising osteolysis of the terminal phalanges, characteristic craniofacial abnormalities, dental anomalies, and proportionate short stature. The clinical and radiological findings develop and progress with age. Here, we report on a HCS patient with severe scoliosis and exceptionally massive dural ectasia. Congenital scoliosis and dural ectasia have not been reported previously in HCS.

Hajdu-Cheney Syndrome: A Report on Successful Halting of Acro-osteolysis.

CASE: The phenomenon of acro-osteolysis often intrigues clinicians and patients alike, as it causes bone resorption. One such condition is Hajdu-Cheney syndrome. We report our experience in identifying and halting the active bone resorption in a patient and his father with 2-year follow-up results. CONCLUSION: Management included identification of the NOTCH2 mutation and treatment with antiresorptive measures. In addition, genetic counseling and antenatal counseling are recommended to explain the risk of inheritance.

A unique case of Hajdu-Cheney syndrome and squamous cell carcinoma of the anus.

OBJECTIVE: Hajdu-Cheney syndrome (HCS), first described in 1948 by Hajdu and independently in 1965 by Cheney, is an extremely rare disorder characterized by severe and excessive bone resorption leading to osteoporosis, with a wide range of other systemic complications from connective tissue and bone dysplasia. Currently there are approximately 50 distinct cases reported in the literature. There have been several reports associating polycystic kidneys with HCS and several other connective tissue disorders, suggesting a possibility of a hyperproliferative component to the syndrome. No articles exist in the current literature describing a case of HCS with concurrent carcinoma. Here, we present a case of a 54-year-old nonimmune compromised woman with multiple stigmata of HCS and recently diagnosed anal squamous cell carcinoma. METHOD: This is a case report of HCS and stage T3N0 squamous cell carcinoma of the anus. RESULTS: This is the first report of a patient with HCS with malignancy. CONCLUSIONS: We present a patient with HCS who developed anal squamous cell carcinoma. The mechanism of HCS, which is still unknown, may either make patients more susceptible to carcinoma or may just be a reflection of the normal incidence of anal squamous cell carcinoma given attributable risk factors.

Bisphosphonate therapy for spinal osteoporosis in Hajdu-Cheney syndrome - new data and literature review.

BACKGROUND: Hajdu-Cheney syndrome (HCS) (#OMIM 102500) is a rare, autosomal dominant condition that presents in early childhood. It is caused by mutations in the terminal exon of NOTCH2, which encodes the transmembrane NOTCH2 receptor. This pathway is involved in the coupled processes of bone formation and resorption. The skeletal features of HCS include acro-osteolysis of the digits and osteoporosis commonly affecting vertebrae and long bones. Fractures are a prominent feature and are associated with significant morbidity. There is no specific treatment, but with both acro-osteolysis and generalized osteoporosis, it is possible that anti-resorptive treatment might be of benefit. However, to date only a few case reports have evaluated the effectiveness of bisphosphonate treatment. METHODS: We describe the clinical features, treatment regimens and response to bisphosphonate treatment in 7 newly described patients aged 6-39 with HCS, and pooled the data with that from 8 previously published cases (a total of 17 courses of treatment in 15 individuals). RESULTS: The mean lumbar spine bone mineral density (BMD) z-score before treatment was - 2.9 (SD 1.2). In 14 courses of treatment (82%), there was an increase in BMD with bisphosphonate treatment, but the impact (in terms of change in spinal BMD z-score) appeared to be less with advancing age (p = 0.01). There was no evidence that acro-osteolysis was prevented. CONCLUSIONS: Although individual response is variable and age-related, the data support a role for bisphosphonates in preventing or treating spinal osteoporosis in HCS, but bone loss from the lumbar spine may be rapid after cessation.

Multicentric carpal-tarsal osteolysis with nephropathy treated successfully with cyclosporine A: a case report and literature review.

Multicentric carpal-tarsal osteolysis is a rare skeletal disorder characterized by osteolysis of the metacarpal, carpal, and tarsal bones and leading to crippling joint deformities. Progressive nephropathy occurs in more than half the cases. All previously reported series with renal biopsies showed only end-stage renal disease on histological examination because of the late presentation to nephrologists. Accurate diagnosis of the underlying renal pathological state therefore has not been possible. We report the first case in which early and sequential renal biopsies were performed. These show the renal lesion to be focal and segmental glomerulosclerosis, which was treated successfully with cyclosporine A.

Periodontitis associated with Hajdu-Cheney syndrome.

BACKGROUND: Hajdu-Cheney syndrome (HCS) is an inheritable, rare disorder of bone metabolism, associated with acro-osteolysis of the distal phalanges, short stature, distinctive craniofacial and skull changes, premature tooth loss, and periodontitis. This report focuses on the periodontal manifestations of HCS. METHODS: A 22-year-old female presented with the characteristic clinical features of HCS, including short stature, small face, prominent epicanthal folds, thin lips, small mouth, and short hands. There were no abnormal biochemical, hematological, or hormonal data. Tests for bone mineral density were indicative of osteoporosis. Cephalometric analysis revealed hypoplasia of the midface and increased cranial base angle; the maxilla and the mandible were set posteriorly. The sella turcica was enlarged, elongated, and wide open with slender clinoids. Hair samples were examined by scanning electron microscopy, and tooth cementum and dentin were evaluated histologically. RESULTS: According to the periodontal evaluation, gingival inflammation was 12.5%, bleeding on probing score was 24%, probing depths averaged 4 to 6 mm, and clinical attachment loss averaged 3 to 6 mm. Class II furcations were found on three teeth. Almost all teeth exhibited pathological mobility of varying degrees. There was a generalized, horizontal bone loss of approximately 50%. Three teeth had to be extracted because of severe localized periodontal destruction. Histologic examination of the dentin and the cementum was normal. CONCLUSIONS: HCS periodontitis is associated with an unpredictable and uneven, rapid rate of periodontal destruction of unknown etiology. Further research is required to identify the role of the possible pathogenic factors involved.

Spontaneous regression of syringomyelia in Hajdu-Cheney syndrome with severe platybasia. Case report.

Hadju-Cheney syndrome (HCS) is a rare autosomal-dominant disorder with variable expressivity. It is characterized by facial dysmorphism, premature tooth loss, osteolysis of distal phalanges, and skull abnormalities. In some cases, progressive platybasia can occur and can lead to Chiari malformation with an obstruction of cerebrospinal fluid flow. To the best of the authors' knowledge, only five cases of HCS-associated syringomyelia have been reported in the literature. Because of the rarity of this association, little is known about its natural history. The authors present the case of a 16-year-old boy affected by HCS. On initial magnetic resonance (MR) imaging, a severe basilar invagination with Chiari malformation and cervicothoracic syringomyelia was documented. The syringomyelia had no clinical manifestations. A repeated MR image demonstrated a spontaneous resolution of the syrinx with no changes in the tonsil or the platybasia. The regression of the syringomyelia was confirmed by a control MR imaging examination performed after a 2-year period. No changes in the patient's clinical conditions were found during the follow-up period. This is the first case of spontaneous regression of the syringomyelia despite a severe platybasia in HCS. It did not appear correlated to a modification of the tonsil's structure or position. This observation illustrates one possible evolution of syringomyelia in the natural history of HCS and raises the question of the potential mechanisms involved in the spontaneous drainage of the syringomyelic cavity.

Hajdu-Cheney syndrome and syringomyelia. Case report.

This 7-year-old boy with Hajdu-Cheney syndrome presented with cervical syringomyelia related to rapidly progressing platybasia. Decompressive craniectomy provided temporary improvement, and his clinical status was eventually stabilized after external immobilization, according to findings at 2.5 years of follow up. In a review of the literature the authors found 57 cases of the syndrome, only three of which were associated with syringomyelia. The youth of the patient, the severe form and rapid course of the disease, and the very specific anatomical conditions related to cranial and facial deformities raised various therapeutic problems.