List of key features Serpentine fibula-polycystic kidney syndrome Hajdu–Cheney syndrome Foetal limb shortening Osteogenesis Chondrocyte differentiation Osteoclastogenesis NOTCH2 Introduction Serpentine fibular polycystic kidney syndrome (SFPKS) is an autosomal dominant disorder caused by a NOTCH2 gene mutation, primarily resulting in bone and kidney abnormalities. The clinical manifestations include a small jaw, cleft palate, delayed motor development, hearing loss, short stature, polycystic kidneys, congenital heart disease, osteolysis, osteoporosis, fractures, and abnormal vertebrae (Currarino, 2009). No definitive treatment exists for this rare condition, and only a few dozen cases have been reported worldwide. Hajdu–Cheney syndrome (HCS) is also caused by a NOTCH2 gene mutation and is characterized by bone resorption and progressive destruction of the distal phalanges, primarily leading to osteoporosis and skull deformities. SFPKS was initially differentiated from HCS by the presence of polycystic kidneys and a serpentine fibula; however, it is now considered part of the phenotypic spectrum of HCS owing to overlapping clinical features and shared mutations in exon 34 of NOTCH2 (Gray et al. , 2012). The varying severity of foetal osteogenic disorders may account for the phenotypic spectrum of HCS; however, only a few reports of HCS and SFPKS include foetal bone findings, and no clear distinction among these disorders has been established. Here, we describe a case of SFPKS in which foetal limb shortening led to early postnatal diagnosis and discuss its place within the HCS spectrum. Clinical summary The female patient was the third child of healthy Chinese parents with no family history of congenital anomalies. Her mother was referred at 17 weeks’ gestation with no notable findings. At 20 weeks, ultrasound revealed indistinguishable radius and ulna, suggesting bilateral forearm shortening, although other parameters were normal (Table 1). At 23 weeks, the ulna measured 22. 5 mm (‐5. 5 SD), radius 21. 9 mm (‐4. 7 SD), and estimated foetal weight (EFW) 566 g (‐0. 4 SD). At 27 weeks, both bones remained short (ulna: 28. 6 mm, ‐5. 5 SD; radius: 29. 2 mm, ‐3. 7 SD). Nuchal translucency was noted; EFW was 1048 g (‐0. 2 SD equivalent for gestational age). Table 1 - Foetal measurements Gestational weeks 20 Weeks 23 Weeks 27 Weeks Femur length 30. 4 mm ‐0. 7 SD Abdominal circumference 16. 19 mm 0. 8 SD Estimated foetal weight 354 g ‐0. 2 SD 566 g ‐0. 4 SD 1048 g ‐0. 2 SD Ulna length 22. 5 mm ‐5. 5 SD 28. 6 mm ‐5. 5 SD Radius length 21. 9 mm ‐4. 7 SD 29. 2 mm ‐3. 7 SD Amniocentesis was performed at 21 weeks after counselling. Fluorescence in-situ hybridisation revealed no trisomy 13, 18, or 21, and chromosomal microarray showed no significant copy number abnormalities. Later, parameters such as biparietal diameter, abdominal circumference, femur length, humeral length, and EFW were within normal limits. Delivery occurred by caesarean section at 37 weeks. Apgar scores were 8 and 9 at 1 and 5 min; umbilical artery pH was 7. 28. Birth weight was 2848 g (0. 88 SD), length 49 cm (0. 65 SD), and head circumference 36 cm (2. 5 SD). The patient had a small jaw, short forearms, a high palate, and flat feet. Radiography revealed mandibular retroflexion (Fig. 1a), anterior lumbar vertebral concavity (Fig. 1b), mild ulnar bowing (Fig. 2), and serpentine fibulae bilaterally (Fig. 3). Echocardiography identified a patent ductus arteriosus and an atrial septal defect. Fig. 1: (a) Lateral skull radiograph at birth demonstrating posterior deflection of the lower jaw. (b) Spine radiograph at birth, showing the concavities of the anterior part of the lumbar vertebrae. Fig. 2: Radiograph of the right arm at birth showing mild bowing of the ulna. Fig. 3: Radiograph of the legs at birth, showing serpentine fibulae. Conservative treatment did not result in weight gain, and poor feeding and tachypnoea because of heart failure from increased pulmonary flow required ductus arteriosus clipping at 22 days. Abdominal ultrasonography showed increased renal echogenicity and indistinct corticomedullary junctions, with multiple cysts appearing by 4 months, consistent with polycystic kidneys. Hearing impairment (60 dB threshold) was detected by auditory brainstem response at 17 days, whereas MRI and electroencephalography were normal. Feeding difficulties related to jaw deformity required nasogastric feeding. She was discharged at 8 months with normal development. By 1 year 3 months, she walked unaided, and nasogastric support was discontinued. At 2 years 8 months, weight was 13. 4 kg (0. 63 SD) and height 94. 0 cm (‐1. 38 SD). She had left leg inversion managed with an orthosis. Ongoing follow-up focuses on renal cyst progression and orthopaedic abnormalities. Investigations The patient and her family members were enrolled in a study approved by Teikyo University Ethical Review Board for Medical and Health Research Involving Human Subjects at Teikyo University Hospital, and informed consent was obtained. As SFPKS was suspected based on clinical findings, genomic DNA was extracted from the patient’s blood using the manufacturer’s standard protocol (Kazusa DNA Research Institute, Kisarazu, Chiba, Japan). A targeted gene panel analysis (JAG1, NOTCH2) was performed, which identified a heterozygous variant NM₀24408. 4: c. 6853del p. (Gln2285ArgfsTer10) NC₀00001. 11: g. 119915872del in NOTCH2 – a gene associated with Alagille syndrome and HCS. This variant was ultrarare and not registered in the Human Gene Mutation Database, ClinVar, the Genome Aggregation Database, or the Japanese Multi-Omics Reference Panel. Notably, the same amino acid variant c. 6854delA p. (Gln2285ArgfsTer10) has previously been reported in HCS (Han et al. , 2015) and is classified as ‘likely pathogenic’ according to the 2015 American College of Medical Genetics and Genomics guidelines (PS1+PM2+PM4+PPP3+PPP4). Discussion Targeted panel analysis revealed a frameshift mutation in exon 34 of NOCTCH2. Over 30 mutations in this exon have been reported as associated with HCS or SFPKS (Narumi et al. , 2013). Approximately 9% of patients with HCS present with bowing fibulae, 14% with polycystic kidney disease, and 12% with congenital heart disease (Narumi et al. , 2013). In our case, we observed foetal limb shortening, which has not been reported before, and SFPKS was diagnosed at 2 months of age based on the newly identified mutation, whole-body radiography, and the presence of congenital heart and polycystic kidney disease. SFPKS is regarded as a subtype of HCS, with the degree of NOTCH2 dysfunction contributing to phenotypic variability in osteogenesis. When mutant NOTCH2 leads to SFPKS or HCS, abnormalities in chondrocyte and osteoclast differentiation can occur (Martin et al. , 2014; Fukushima et al. , 2017; Isojima and Sims, 2021). An autopsy case of SFPKS demonstrated abnormal chondrocyte differentiation with shortened femora observed at 19 weeks. Histological analysis of the femoral growth plate revealed poor transition from prehypertrophic to hypertrophic chondrocytes (Martin et al. , 2014). This defect explains limb shortening and short stature, as disruption of the hypertrophic phase inhibits linear bone growth. Fukushima et al. (2017) reported that NOTCH2 HCS mutations lead to hyperosteoclast activity, increased bone resorption exceeding osteogenesis, delayed cortical bone maturation, and bone bowing. A mouse model with a heterozygous NOTCH2 mutation confirmed trabecular and cortical osteopenia with enhanced osteoclastogenesis and bone resorption (Isojima and Sims, 2021). Bowing of fibulae and ulnae was described in both the autopsy case (Martin et al. , 2014) and in our patient. Phenotypic heterogeneity has been reported in identical mutations, reflecting variable effects on chondrocyte differentiation and osteoclastogenesis. Further studies on osteogenic differentiation are needed to clarify the mechanisms underlying HCS and its phenotypic subtypes. Acknowledgements We express our sincere gratitude to the patient and her parents for their participation in this study and for granting permission to publish clinical images. We also extend our thanks to Dr Gen Nishimura and the Japanese Skeletal Dysplasia Consortium for their valuable contribution to the radiographic diagnosis. The patient and her family members were enrolled in an institutional review board-approved study at Teikyo University Hospital, and informed consent was obtained. Informed consent has been obtained from patients that grants permission for the publication of images as part of this work. The data supporting the findings of this study are available from the corresponding author upon reasonable request. These data are not publicly available owing to privacy and ethical restrictions and were therefore not deposited in a public repository. Conflicts of interest There are no conflicts of interest.
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