The portal for rare diseases and orphan drugs

Less than 100 cases are confirmed to date.

Whilst affected individuals may appear normal at birth and during infancy, minor facial abnormalities, such as a small mandible, may come to clinical attention in half of affected infants. With age, affected children develop facial dysmorphism (dolicho-bathrocephaly, coarse hair, synophrys, hypertelorism, downslanting palpebral fissures, low set ears, midface flattening, long philtrum, and micrognathia). The fontanels are delayed in closure. Short stature manifests in early childhood and is progressive, presumably due to vertebral compression. Acroosteolysis becomes manifest between preschool age and mid-childhood and clinically presents as short finger tips and nails with pseudoclubbing. Osteoporosis is evident even in childhood, but is conspicuously progressive in late adolescent to adulthood, leading to biconcave codfish vertebrae and kyphoscoliosis. Bone weakness at the craniovertebral junction causes platybasia and basilar invagination, resulting in syringomyelia, hydrocephalus and neurologic deficits. Dental anomalies include severe crowding, periodontitis, and premature loss of teeth. Some patients are at potential risk of renal failure due to multiple renal cysts. Serpentine fibula-polycystic kidney syndrome (SFPKS) is the most severe manifestation of Hajdu-Cheney syndrome, which manifests with bent (serpentine) fibulae and radii as well as congenital renal cysts.

The disorder is caused by heterozygous pathogenic variants in the NOTCH2 gene mapped on 1p12 and encoding the neurogenic locus notch homolog protein 2 (Notch2). All known disease-causing variants are located in exon 34, and cause abnormally increased Notch2 signaling (gain-of-function). Of note, pathogenic variants in NOTCH2 also cause a different malformation syndrome, Alagille syndrome type 2.

The diagnosis is made on clinical and radiological grounds, and is confirmed by molecular detection of pathogenic variants in the NOTCH2 gene.

The facial abnormalities are commonly misdiagnosed with Noonan syndrome in infancy and early childhood. The differential diagnosis includes genetic syndromes with pediatric acroosteolysis, such as pyknodysostosis, mandibuloacral dysplasia, as well as congenital insensitivity to pain.

Prenatal diagnosis is theoretically possible in affected families in which the causal NOTCH2 variant has been previously identified. The fetal manifestation of SFPKS can be detected on prenatal ultrasonography.

The pattern of inheritance is autosomal dominant. The offspring of an affected individual is at a 50% risk of having the pathogenic variant in NOTCH2. However, most cases are sporadic in occurrence.

Only symptomatic treatment is available for the specific symptoms. Bisphosphonate therapy is beneficial for osteoporosis, though it is not helpful for acroosteolysis. Individuals with renal failure require the standard medical intervention. Regular dental examinations are important.

The life expectancy of patients is not severely impaired. Osteoporosis and associated fractures cause significant morbidity. Basilar invagination occasionally leads to syringomyelia and seldom hydrocephalus. Dental management is important for the quality of life.