Hajdu-Cheney syndrome with a novel variant in NOTCH2 gene: A case report

Abstract

Introduction

Hajdu-Cheney syndrome is a rare disorder caused by truncation mutations in exon 34 of the NOTCH2 gene. The main presentation includes acro-osteolysis, osteoporosis, and dysmorphism. This syndrome affects the other body systems as well.

Case presentation

We report a case of a 6-year-old female that initially developed polyhydramnios and short upper limbs as a fetus. In addition, the patient had multiple anomalies as a neonate, including dysmorphism, congenital heart disease, hearing loss, recurrent respiratory tract infections, skeletal abnormalities, renal cysts, and hypertension. She continues to receive multidisciplinary care, and the finding of a C.7021C > T: P.Q2341x mutation in exon 34 of the NOTCH2 gene confirms the diagnosis. To our knowledge, this is the first case to report this variant in the literature.

Discussion

Because of the rarity of this syndrome and its diverse presentation, a high index of suspicion accompanied by genetic testing is paramount for diagnosing Hajdu-Cheney syndrome. We recommend a multidisciplinary approach for these patients to provide the highest possible quality of care.

Highlights

• •The case had several defects and dysmorphisms during NICU admission.
• •Sequencing revealed a novel mutation in exon 34 of NOTCH2 gene, consistent with HCS.
• •The patient is repeatedly admitted to the PICU due to hypoxemic respiratory failure.
• •She suffers from failure to thrive with height and weight below the third percentile.
• •Diagnosing Hajdu-Cheney syndrome is challenging due to its rarity and complexity.

1. Introduction

Hajdu-Cheney syndrome is a rare skeletal disease that follows an autosomal dominant inheritance. Nevertheless, several reports described sporadic cases as well. The genetic mutations behind the disorder result in the truncation of exon 34 of the NOTCH2 gene located on chromosome 1p12 (Isidor et al., 2011). Acro-osteolysis and osteoporosis seem to be the main features of the syndrome, aside from other skeletal abnormalities and dysmorphic features (Elias et al., 1978; Leidig-Bruckner et al., 1999; Letchumanan et al., 2009; Nunziata et al., 1990; Rosenmann et al., 1977). The clinical presentation is variable as it is a multi-systemic disease (Brennan and Pauli, 2001; Cortés-Martín et al., 2020). Reported renal anomalies include renal cysts, hypertension, and end-stage renal disease. Cardiovascular and respiratory systems wise, acyanotic congenital heart diseases and recurrent respiratory infections are commonly documented in the literature. Otological, ocular, neurological, and dental disorders are reported in these patients as well (Ahmed et al., 2021). Owing to the variable presentation of these patients, the management is tailored to their needs, and currently, there is no lifelong cure. We report a rare case of Hajdu Cheney syndrome in Saudi Arabia with a novel pathogenic NOTCH2 variant.

2. Case

The case is a 6-year-old Saudi girl born at a gestational age of 32 + 3 weeks due to preterm labor as part of a dichorionic-diamniotic in vitro fertilization (IVF) twin pregnancy. The family history is negative for genetic diseases. Prenatal ultrasound during the pregnancy was remarkable for polyhydramnios and shortened long bones in the forearms of our case, in addition to reduced interval growth in her twin brother. She also exhibited a progressive decline of the fetal femur length in relation to the standard deviation, becoming below the 5th percentile at 32 + 3 weeks of gestational age. Immediately after birth, our case developed respiratory distress syndrome, and thus she was admitted to the neonatal intensive care unit (NICU), where she required two doses of surfactant and respiratory support. Her APGAR scores were 8 and 9 at 1 and 5 min, respectively. Her birth weight was 1.63 kg, her birth height was 41.5 cm, and her head circumference was 29.5 cm.

During her stay in the NICU, the routine cardiac echocardiogram revealed a small atrial septal defect, a small perimembranous ventricular septal defect, and a large patent ductus arteriosus with bidirectional shunting. The patent ductus arteriosus was surgically repaired through left lateral thoracotomy. At two days of age, a screening abdominal ultrasound was performed, which came back negative for any abnormalities. Two months later, the repeated ultrasound revealed multiple new renal parenchymal cysts with increased renal parenchymal echogenicity. Doppler ultrasound showed normal renal arteries and veins. She developed secondary hypertension that was treated with 0.6 mg captopril twice daily; however, her kidney function test results were unremarkable.

The newborn examination revealed micrognathia, hypertelorism, low-set ears, a high-arched soft palate, bifid uvula, short arms, and lanugo hair. Moreover, the patient suffered from recurrent upper and lower respiratory tract infections during admission. In addition, the patient had reduced sucking skills and prolonged feeding time, necessitating a follow-up with the speech pathologist. She also had hemolytic disease of the newborn secondary to ABO incompatibility that was managed with double phototherapy. Tandem mass spectrometry, urine gas chromatography–mass spectrometry (Urine GC–MS), very long-chain fatty acids (VLCFA) analysis, ammonia levels, and lactate dehydrogenase (LDH) levels were all unremarkable. Blood samples were obtained for single nucleotide polymorphism (SNP) microarray and whole exome sequencing (WES).

A radiographic skeletal survey (Fig. 1) showed mild diffuse osteopenia, thinning of the calvarium, open skull sutures, and mild mid-face hypoplasia. Additionally, bilateral mesomelic shortening of the forearm bones was reported. In the lower limbs, the radiographs showed bowed and longer fibulae, accompanied by mildly shorter tibiae bilaterally. Additionally, there is a mild asymmetric shortening of the phalanges of both feet, most prominently affecting the proximal phalanges of the first toes. Lastly, non-displaced fractures associated with a mild periosteal reaction were detected in the left tibia and both humeri. The findings in the skeletal survey and the abdominal ultrasound made polycystic kidneys serpentine fibula syndrome the most likely differential diagnosis at the time. She didn't pass the hearing screening and was discharged after months of NICU stay.

Fig. 1.

Radiological survey of a newborn Hajdu-Cheney syndrome patient. A Showing mild diffuse osteopenia, thinning of the calvarium, and mild midface hypoplasia. B showing mesomelic shortening of the left forearm bones, especially affecting the left radius. C showing bowing of the fibula in addition to a non-displaced fracture of the tibia in the left leg. D showing mild asymmetric shortening of the phalanges of both feet. E showing a non-displaced fracture of the left proximal humerus.

Upon follow-up, she is admitted recurrently to the pediatric intensive care unit (PICU) due to recurrent respiratory tract infections and resultant hypoxemic respiratory failure. Because she suffers from reactive airway disease, the patient was started on 0.5 mg budesonide nebulizer twice daily and 2.5 mg albuterol nebulizer as needed. She used to follow up with the speech and language pathologist for her inability to tolerate solid and semisolid foods and her language delay; however, these concerns had been resolved. The audiometry revealed bilateral, moderate, sensorineural hearing loss, for which she uses hearing aids. In addition, the patient underwent a bilateral myringotomy procedure with ventilation tube insertion due to chronic otitis media with effusion. She also suffers from recurrent tonsillitis treated with antibiotics.

Regarding her lower limbs, she demonstrated a full range of motion on all joints, an acceptable mechanical axis, an insignificant limb length discrepancy, and no limping on her visits. Whole exome sequencing revealed a heterozygous C.7021C > T: P.Q2341x mutation in exon 34 of the NOTCH2 gene, which was classified as pathogenic for Hajdu-Cheney Syndrome (HCS) following the ACMG guidelines. The genetic test results of her non-consanguineous parents were negative for the mutation, indicating a de novo mutation. Furthermore, she was found to have mild myopic astigmatism and hirsutism. Magnetic resonance imaging (MRI) of the brain at 22 months of age revealed a partially empty sella turcica; however, her ACTH, cortisol, TSH, T4, IGF-1, and IGF-BP3 levels were within the normal range. Furthermore, the glucagon and clonidine growth hormone stimulation test results were normal.

At three years of age, the parents were concerned that she suffered a tibial fracture following a mild trauma. A dual-energy X-ray absorptiometry (DXA) scan was ordered in October 2020. The scan results detected a lumbar spine Z-score of −5.0 and a whole-body z-score of −4.7. She was diagnosed with osteoporosis and started on 0.05 mg/kg IV zoledronic acid every six months in addition to vitamin D3 and calcium supplements. In the following DXA scan performed in November 2021, the lumbar spine and whole-body z-scores were −3.8 and −3.1, respectively. The reference population for the performed DXA scans (GE Healthcare Lunar Prodigy System) is the USA combined NHANES/Lunar reference population (V112). Z-scores were calculated based on the reference values for her age, sex, and ethnicity; however, no adjustments were performed for her short stature.

She has been suffering from failure to thrive, for which she depends on a gastrostomy feeding tube and oral feeding. She is on Enalapril for hypertension, with a current dose of 4 mg once daily. Recent blood tests revealed that she suffers from iron deficiency anemia and therefore, she was prescribed 25 mg ferrous sulfate oral drops twice daily. A performed X-ray of the thoracolumbar spine in February 2023 showed normal alignment of the thoracolumbar spine with no evidence of fractures, spondylitis, or spondylolisthesis. At the moment, there are no convincing features of acro-osteolysis in imaging. Her current height is 91 cm (below the third percentile), and her current weight is 11.1 kg (below the third percentile) (Fig. 2). She is currently attending kindergarten with a good performance. Her twin brother is growing normally and is medically free.

Fig. 2.

Growth charts of a Hajdu-Cheney syndrome patient who suffers from failure to thrive.

3. Discussion

Genetic studies were able to detect nonsense and deletion mutations in the terminal exon of the NOTCH 2 gene as the cause of Hajdu-Cheney syndrome (Isidor et al., 2011). The resultant gain of function of the NOTCH 2 receptor protein causes continuous signaling of the NOTCH signaling pathway. NOTCH pathway is involved in cellular differentiation and osteoclastogenesis (Fukushima et al., 2008). Several nucleotide mutations were identified as pathogenic for HCS (Aida et al., 2022). However, this publication is the first to report the C.7021C > T: P.Q2341x variant in exon 34 of the NOTCH2 gene as pathogenic for Hajdu-Cheney syndrome.

Also known as acroosteolysis with osteoporosis and changes in skull and mandible syndrome, HCS's hallmark features include acroosteolysis, osteoporosis, and other skeletal anomalies. Additionally, the syndrome has been reported to affect other organs, noticeably the heart, kidneys, ears, eyes, and teeth (Ahmed et al., 2021; Brennan and Pauli, 2001; Cortés-Martín et al., 2020). Our patient is following up with multiple subspecialty clinics for bilateral renal cysts, hypertension, bilateral hearing loss, osteoporosis, failure to thrive, iron deficiency anemia, reactive airway disease, and recurrent respiratory tract infections. This phenotype has been commonly reported in other Hajdu-Cheney syndrome patients.

With less than 100 cases reported in the literature, the diagnosis of Hajdu-Cheney syndrome can be delayed and even misdiagnosed in clinical practice. Furthermore, the variable phenotypes and broad spectrum of clinical findings can make it challenging to reach the diagnosis. Our case's neonatal admission course of dysmorphic features, large patent ductus arteriosus, polycystic kidneys, hypertension, and hearing loss were all detected and managed appropriately during her NICU stay. It is worth mentioning that the abnormalities found on the x-ray and the renal cysts discovered on sonographic imaging have raised suspicions about the diagnosis of serpentine fibula polycystic kidney syndrome at two months of age. This syndrome is now considered a phenotypic variant of Hajdu-Cheney syndrome (Gray et al., 2011).

With a prevalence of less than 1 in 1,000,000 live births, there is a lack of studies focusing on the quality of life and the overall prognosis of Hajdu-Cheney syndrome patients (Cortés-Martín et al., 2020). Generally, the deformities progress with advancing age, eventually resulting in disability and lifelong pain (Descartes et al., 2014; Jirečková et al., 2018). According to our literature review, milder phenotypes of Hajdu-Cheney syndrome could procreate, albeit it's common for the offspring to be affected as a result of the autosomal dominant nature of the syndrome (Ahmed et al., 2021; Descartes et al., 2014; Efstathiadou et al., 2020; Narumi et al., 2013).

CRediT authorship contribution statement

Mariam Abdelkarim: Writing – original draft, Writing – review & editing, Methodology. Dalal Alageel: Writing – original draft, Writing – review & editing. Faridul Ahsan: Writing – original draft, Writing – review & editing. Raghad Alhuthil: Writing – review & editing, Resources. Haifa Alsarhani: Writing – review & editing, Resources. Afaf Alsagheir: Supervision, Writing – review & editing, Investigation, Resources.

Declaration of competing interest

The authors state that they do not have any competing interests.

Data availability

The datasets used in the current study are available from the corresponding author upon reasonable request.