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

Abstract

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.

Hajdu-Cheney Syndrome: Report of a Case in Spain

“…The phenotypic variability [8,27,28], a consequence of the variability of expression of NOTCH2, is evident when comparing this case to other cases diagnosed with HCS that have been published in the scientific literature. Cases such as those presented by Swan et al [29], Ades et al [12] and Takatani et al [30] all show differences in their physical appearance and clinical presentation despite having the same diagnosis.…”

Clinical and neurodevelopmental outcome of prenatally diagnosed Wormian bones

“…Some reports consider this entity as either a normal variant or an acquired condition secondary to head trauma and skull manipulations as practiced in some cultures. 1,2 Other studies have found an association of this phenomenon with skeletal dysplasia, 6,9 osteogenesis imperfecta, 2,4,12 and craniosynostosis 2,21,22 and also with rare conditions such as Menkes Disease, 23 Robinow Syndrome, 7 Primrose Syndrome 9 and ARID2 mutations. 10,24 The current study provides an informative description of this condition in a cohort of 72 fetuses.…”

Hajdu‐Cheney syndrome with atypical cardiovascular abnormalities

“…With similar molecular and clinical findings in Serpentine fibula‐polycystic kidney syndrome and Hajdu‐Cheney syndrome, it is now accepted that the two syndromes are variable manifestations of the same mutated gene and so are the same disorder. Cardiovascular findings by Kaler et al (1990) were mostly valvular abnormalities (mitral and aortic) whereas the cardiovascular manifestations in all subsequent reports of Hajdu‐Cheney syndrome have been cardiac defects (Table 1) (Albano et al, 2007; Gray et al, 2012; Rosser et al, 1996; Sargin et al, 2013; Zeng et al, 2020). In the seven cases of Hajdu‐Cheney documented with cardiovascular manifestations, four had PDA with two associated with ventricular septal defect (VSD) and one with atrial septal defect (ASD).…”