Alternative titles; symbols
SNOMEDCT: 63122002; ORPHA: 955; DO: 2736;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p12 | Hajdu-Cheney syndrome | 102500 | Autosomal dominant | 3 | NOTCH2 | 600275 |
A number sign (#) is used with this entry because of evidence that Hajdu-Cheney syndrome (HJCYS) is caused by heterozygous mutation in the NOTCH2 gene (600275) on chromosome 1p12.
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).
Hajdu and Kauntze (1948) reported a 37-year-old man with basilar impression, craniofacial and peripheral dysostosis, together with spinal osteoporosis and chondrodystrophy, which they noted for the rarity of the combined changes.
Cheney (1965) described this connective tissue disorder in a family living in the upper peninsula of Michigan. The mother and 4 children had acroosteolysis, multiple wormian bones, and hypoplasia of ramus of mandible. Unlike pycnodysostosis (265800), a recessive with osteosclerosis, the condition in Cheney's patients included osteoporosis with basilar impression as a feature. The mother was 57 and the affected children (4 of 6) were 35, 26, 21 and 13 years of age. Dorst and McKusick (1969) described a case.
Herrmann et al. (1973) exhaustively reviewed the previously reported cases and described 1 new case. They pointed out that the changes in the terminal phalanges in this condition as well as in pycnodysostosis are 'pseudo-osteolysis,' that is, the disorder is one of defective development of bone rather than destruction of bone already formed. They observed that acroosteolysis, generalized osteoporosis and multiple fractures of the skull, spine and digits, short stature, persistent cranial sutures, multiple wormian bones, early loss of teeth, and joint laxity were features associated in varying degrees. The authors suggested the name arthrodentoosteodysplasia and the eponym Hajdu-Cheney syndrome for this disorder. The patients show bathrocephaly (projection of the occipital area and a deep groove at the lambdoidal sutures between the occipital and parietal bones). Loose-jointedness, dislocations of the patella, and hernia may also occur. Some have suggested that short stature is a consistent feature. In addition to micrognathia and narrow high palate, prominent ears may be a feature. Unusually deep voice has also been noted.
Silverman et al. (1974) provided useful long-term follow-up on 2 cases. They believed the patient reported by Gilula et al. (1976) had a nonfamilial disorder.
Elias et al. (1978) reported Cheney syndrome in a mother and son, one of whom had an enlarged sella turcica associated with normal endocrine function. Histologic studies made in an area of active osteolysis in a phalanx suggested to the authors 'a neurovascular dysfunction with local release of osteolytic mediators.' Matisonn and Ziady (1973) described affected father and 2 sons; only the sons were personally examined.
Udell et al. (1986) found this disorder in a 27-year-old man who for 7 years had gradually progressive loss of distal phalangeal mass with pain in the affected fingers. His mother had similar 'shrinking fingers,' which first appeared at about age 50, progressed for 2 years, and then became asymptomatic. Udell et al. (1986) were impressed with the abundance of mast cells in the affected tissues and suggested that these cells might be elaborating a local factor causing or promoting osteolysis. They pointed to the osteopenia that occurs with large doses of heparin and with systemic mast cell disease (154800).
Magnetic resonance imaging was reported by Kawamura et al. (1991).
O'Reilly and Shaw (1994) gave an extensive description of the radiologic features in a 15-year-old girl. From early in life, the face was dysmorphic with a prominent premaxilla, hypertelorism, and downward sloping eyes with narrow palpebral fissures. Joint laxity and hyperextensibility developed as the child grew older. Height and weight remained at the third percentile for age but head circumference was above the 98th percentile, with an enlarged pituitary fossa on skull radiographs. Kyphoscoliosis required bracing and eventually spinal fusion. The permanent teeth were all lost soon after eruption. Basilar impression with multiple wormian bones and osteolysis of the terminal phalanges with overlying soft tissue swelling were illustrated.
Brennan and Pauli (2001) described 6 affected individuals in 2 families with Hajdu-Cheney syndrome and reviewed the literature on previously reported cases. Most of the 57 cases analyzed had acroosteolysis and concomitant digital abnormalities. Other features found in more than half of affected individuals included short stature, micrognathia, abnormal dentition, joint hypermobility, wormian bones, open sutures of the skull, platybasia, sellar and clivus abnormalities, and decreased bone density. Marked variability in the number and severity of clinical features was noted. Clinical problems and physical features changed over time and often progressed with age. The authors reviewed major medical concerns that may be observed at different ages, including renal abnormalities at birth and during infancy, multiple fractures and recurrent infections in early childhood, and neurologic symptoms and joint abnormalities in adulthood.
Ades et al. (1993) described a child with HJCYS complicated by basilar invagination and hydrocephalus. MRI showed Arnold-Chiari malformation and obstruction to cerebrospinal fluid flow at the level of the foramen magnum. A ventriculoperitoneal shunt was inserted at the age of 10 years.
Kaler et al. (1990) described a 21-year-old woman with Hajdu-Cheney syndrome who had severe mitral regurgitation and mild aortic stenosis necessitating mitral valve replacement and aortic valvotomy at the age of 14 years. Pathologic examination of the mitral valve showed myxomatous degeneration with thickened valve leaflets and foci of calcification. At the age of 18, pacemaker implantation was necessitated by the development of heart block. At the age of 20, balloon aortic valvuloplasty was attempted for worsening aortic stenosis, but was unsuccessful because of thick and calcified valve leaflets; aortic valve replacement was required.
Clinical Variability: Serpentine Fibula-Polycystic Kidney Syndrome
Dereymaeker et al. (1986) described 3 female patients with features of the skeletal dysplasia Melnick-Needles syndrome (MNS; 309350). However, 1 patient differed from the other patients by elongation and S-shape ('serpentine'-shape) of the fibulas, suggesting heterogeneity. Fryns (1997) reported follow-up of the patient reported by Dereymaeker et al. (1986) who had the S-shape fibulas. At age 18 years, she had developed seizures resulting in progressive hemiplegia, cystic kidneys, and progressive hearing loss. She died at age 21 of renal failure and grand-mal seizures. Fryns (1997) concluded that the serpentine fibula syndrome and Hajdu-Cheney syndrome are variable manifestations of the same mutated gene.
Exner (1988) observed a 5-year-old girl with small stature, unusual facial appearance, normal intelligence, polycystic kidneys, and S-shaped and elongated fibulas. He noted the striking similarities to the patient with serpentine fibulas reported by Dereymaeker et al. (1986), and postulated a hitherto unrecognized syndrome distinct from Melnick-Needles syndrome.
Majewski et al. (1993) reported a 9.5-year-old girl who showed proportionate short stature, large skull with an occipital depression, shield chest with mild pectus excavatum and wide intermamillary distance, hirsutism, short neck, bowed forearms and lower legs due to bowed radii and elongated serpentine fibulas, and metatarsus adductus. Two of the 3 reported patients, including the patient of Majewski et al. (1993), were deaf. For comparison and contrast, Majewski et al. (1993) also reported a girl with Melnick-Needles syndrome. Chromosomes were normal. The photographs of the patient with serpentine fibulas showed an appearance suggesting Turner syndrome with low-set ears and short neck. Majewski et al. (1993) suggested that the disorder, which they referred to as serpentine fibula-polycystic kidney syndrome (SFPKS), was distinct from Melnick-Needles syndrome. The mode of inheritance of SFPKS was unclear; because all reported cases had been female, X-linked dominant with lethality in the hemizygous affected male was postulated.
On the basis of 2 unrelated patients with typical Hajdu-Cheney syndrome and cystic kidneys with ultrasonographic changes similar to those of autosomal dominant polycystic kidney disease (173900), Kaplan et al. (1995) concluded that cystic kidneys are an important component of this disorder. Neither patient had a family history of polycystic kidney or Hajdu-Cheney syndrome. One of the patients died of complications of the latter condition at the age of 16 years. Kaplan et al. (1995) suggested that SFPKS and Hajdu-Cheney syndrome are fundamentally the same disorder.
Rosser et al. (1996) reported 3 sibs with similar manifestations in a family from England. Serpentine fibula, full cheeks, prominent eyes, megalocornea, ptosis, micrognathia, joint laxity, sensorineural deafness, hypoplastic terminal phalanges of the 2nd and 5th fingers, atrial septal defect (ASD), patent ductus arteriosus (PDA; see 607411), and intestinal malrotation were found in the female proband. Her older brother, who died at the age of 8 months, also had micrognathia, full cheeks, megalocornea, and ASD. In addition, he had wide metopic suture, coloboma of the iris, ventricular septal defect, small penis, inguinal hernia, and hypospadias. His karyotype was 47,XXY. Another brother, who died at the age of 15 weeks, had full cheeks, micrognathia, hypoplasia and bowing of the upper parts of both radii and ulnae, PDA, intestinal malrotation, umbilical hernia, and cystic kidneys. Although it is evident that all 3 sibs had various manifestations of the same syndrome, serpentine fibula was found only in the female proband. Because serpentine fibula is not a mandatory manifestation of this syndrome, some other reports from the literature (ter Haar et al., 1982; Hamel et al., 1995) may actually describe the same syndrome. Occurrence of this complex in 3 sibs of different sex suggested autosomal recessive inheritance of the syndrome (Rosser et al., 1996). Maas et al. (2004) concluded that the cases of Rosser et al. (1996) probably represented the same entity that they referred to as the Frank-ter Haar syndrome (249420).
Gray et al. (2012) provided follow-up of the girl reported by Rosser et al. (1996), who was found to have HJCYS by molecular analysis (600275.0008). Between 8 and 12 years, she showed mild developmental delay and progressive pulmonary disease requiring supplemental oxygen and corticosteroid treatment. Facial dysmorphism included narrow hirsute forehead, low posterior hairline, shallow supraorbital ridges, horizontal palpebral fissures, a convergent squint, a pinched nasal bridge with a wide nose, a small mouth, dental malocclusion, low-set posteriorly rotated ears, and prominent maxillae. She had short stature, acroosteolysis, osteoporosis, and stress fractures of the metatarsals bilaterally.
Fryns et al. (1997) described a cystic renal disease with end-stage renal failure, diagnosed at the age of 14 years in a man who was aged 36 at time of report. The patient also had progressive respiratory problems, with Cheyne-Stokes respiration and bilateral vocal cord paralysis. Fryns et al. (1997) concluded that the serpentine fibula-polycystic kidney syndrome is fundamentally the same disorder as Hajdu-Cheney syndrome.
During follow-up of a girl originally reported by Albano et al. (2007) as having serpentine fibula-polycystic kidney syndrome, Gray et al. (2012) found features of Hajdu-Cheney syndrome. At age 8 years, she had persistent ductus arteriosus, ventricular septal defect and facial dysmorphism, including a thin upper lip, downturned mouth, wide nasal tip, long and flat philtrum, dysplastic and posteriorly rotated ears, and short neck. She had bilateral sensorineural hearing loss. Skeletal studies showed wormian bones, vertebral abnormalities, and serpentine fibulae. Ultrasound examination showed polycystic kidneys, but renal function was normal. At age 18 years, she had short stature, hypothyroidism, bathrocephaly, and irregular tooth positioning. There was not significant acroosteolysis of the hands or feet, but she had mild thinning of the distal phalanges. Brain MRI scan showed basilar invagination and abnormal curvature of the cervical spine without cord compression. Intelligence was normal.
Hajdu-Cheney syndrome is an autosomal dominant disorder (Brennan and Pauli, 2001).
Simpson et al. (2011) performed whole-exome sequencing of 3 unrelated individuals of European origin with Hajdu-Cheney syndrome and identified 3 different truncating mutations in exon 34 of the NOTCH2 gene. One of the patients had affected relatives, and the mutation (600275.0003) was found to segregate with the disorder in that family. Further analysis of exon 34 of the NOTCH2 gene identified 11 more truncating mutations in 11 additional probands with the disorder, including 8 patients with sporadic disease who had de novo mutations (see, e.g., 600275.0004-600275.0005). All the mutations occurred in exon 34, the last exon of the NOTCH2 gene, and all were predicted to lead to premature termination before complete translation of the PEST domain, which mediates proteosomal destruction of the protein. The mutations escaped nonsense-mediated mRNA decay, and the truncated proteins were expressed. Thus, the mutations resulted in persistence of the Notch intracellular signal, consistent with a gain of function.
Simultaneously and independently, Isidor et al. (2011) used exome sequencing to identify 5 different truncating mutations in exon 34 of the NOTCH2 gene (see, e.g., 600275.0006-600275.0007) in 5 unrelated probands with Hajdu-Cheney syndrome. The mutant mRNAs were expected to be stable and result in truncated proteins with constitutively active intracellular domains.
Majewski et al. (2011) identified 6 different heterozygous truncating mutations in the NOTCH2 gene in affected members of 7 families with Hajdu-Cheney syndrome. Mutations in the first 3 families were found by whole-exome sequencing. The mutations were all clustered in exon 34 near the C terminus. Functional studies of the variants were not performed.
Gray et al. (2012) identified heterozygous truncating mutations in exon 34 of the NOTCH2 gene (600275.0008 and 600275.0009) in 2 unrelated patients with phenotypic features of both serpentine fibula-polycystic kidney syndrome and Hajdu-Cheney syndrome. The patients had previously been reported by Rosser et al. (1996) and Albano et al. (2007), respectively. The phenotypic overlap between HJCYS and SFPKS had been noted before by Kaplan et al. (1995) and Ramos et al. (1998), both of whom suggested that the 2 disorders may be allelic. The mutations identified by Gray et al. (2012) were located in the same gene region as mutations that cause HJCYS, with the same activating effect on protein function. The molecular findings indicated that SFPKS should be considered part of the phenotypic spectrum of HJCYS.
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