Osteopathia Striata with Cranial Sclerosis (OSCS) is a rare genetic condition primarily characterized by metaphyseal striations of long bones, bone sclerosis, macrocephaly, and other congenital anomalies. It is caused by pathogenic variants in AMER1, a tumor suppressor and a WNT signaling repressor gene with key roles in tissue regeneration, neurodevelopment, tumorigenesis, and other developmental processes. While somatic AMER1 pathogenic variants have frequently been identified in several tumor types (e.g., Wilms tumor and colorectal cancer), whether OSCS (i.e., with AMER1 germline variants) is a tumor predisposition syndrome is not clear, with only nine cases reported with tumors. We here report the first case of neuroblastoma diagnosed in a male child with OSCS, review all previously reported tumors diagnosed in individuals with OSCS, and discuss potential tumorigenic mechanisms of AMER1. Our report adds to the accumulating evidence suggesting OSCS is a tumor predisposition condition, highlighting the importance of maintaining a high index of suspicion for the associated tumors when evaluating patients with OSCS. Importantly, Wilms tumor stands out as the most commonly observed tumor in OSCS patients, underscoring the need for regular surveillance.

Osteopathia Striata with Cranial Sclerosis (OS-CS), also known as Horan-Beighton Syndrome, is a rare genetic disease; about 90 cases have been reported to date. It is associated with mutations (heterozygous for female subjects and hemizygous for males) of the AMER1 gene, located at Xq11.2, and shows an X-linked pattern of transmission. Typical clinical manifestations include macrocephaly, characteristic facial features (frontal bossing, epicanthal folds, hypertelorism, depressed nasal bridge, orofacial cleft, prominent jaw), hearing loss and developmental delay. Males usually present a more severe phenotype than females and rarely survive. Diagnostic suspicion is based on clinical signs, radiographic findings of cranial and long bones sclerosis and metaphyseal striations, subsequent genetic testing may confirm it. Hereby, we report on a female newborn with frontal and parietal bossing, narrow bitemporal diameter, dysplastic, low-set and posteriorly rotated ears, microretrognathia, cleft palate, and rhizomelic shortening of lower limbs. Postnatally, she manifested feeding intolerance with biliary vomiting and abdominal distension. Therefore, in the suspicion of bowel obstruction, she underwent surgery, which evidenced and corrected an intestinal malrotation. Limbs X-ray and skull computed tomography investigations did not show cranial sclerosis and/or metaphyseal striations. Array-CGH analysis revealed normal findings. Then, a target next generation sequencing (NGS) analysis, including the genes involved in skeletal dysplasias, was performed and revealed a de novo heterozygous nonsense mutation of the AMER1 gene. The patient was discharged at 2 months of age and included in a multidisciplinary follow-up. Aged 9 months, she now shows developmental and growth (except for relative macrocephaly) delay. The surgical correction of cleft palate has been planned. Our report shows the uncommon association of intestinal malrotation in a female newborn with OS-CS. It highlights that neonatologists have to consider such a diagnosis, even in absence of cranial sclerosis and long bones striations, as these usually appear over time. Other syndromes with cranial malformations and skeletal dysplasia must be included in the differential diagnosis. The phenotypic spectrum is wide and variable in both genders. Due to variable X-inactivation, females may also show a severe and early-onset clinical picture. Multidisciplinary management and careful, early and long-term follow-up should be offered to these patients, in order to promptly identify any associated morbidities and prevent possible complications or adverse outcomes.

Germline pathogenic variants in AMER1 cause osteopathia striata with cranial sclerosis (OSCS: OMIM 300373), an X-linked sclerosing bone disorder. Female heterozygotes exhibit metaphyseal striations in long bones, macrocephaly, cleft palate, and, occasionally, learning disability. Male hemizygotes typically manifest the condition as fetal or neonatal death. Somatically acquired variants in AMER1 are found in neoplastic tissue in 15-30% of patients with Wilms tumor; however, to date, only one individual with OSCS has been reported with a Wilms tumor. Here we present four cases of Wilms tumor in unrelated individuals with OSCS, including the single previously published case. We also report the first case of bilateral Wilms tumor in a patient with OSCS. Tumor tissue analysis showed no clear pattern of histological subtypes. In Beckwith-Wiedemann syndrome, which has a known predisposition to Wilms tumor development, clinical protocols have been developed for tumor surveillance. In the absence of further evidence, we propose a similar protocol for patients with OSCS to be instituted as an initial precautionary approach to tumor surveillance. Further evidence is needed to refine this protocol and to evaluate the possibility of development of other neoplasms later in life, in patients with OSCS.

Osteopathia striata with cranial sclerosis is a rare X-linked disorder. It is often lethal in male patients, and is considered X-linked dominant since affected females exhibit clinical signs, although milder than males. We describe here an adult male patient, with clinical and radiological signs similar to those described in female patients. Diagnosis was confirmed by the identification of an AMER1 mutation. The presence of long bones striation and the clinical phenotype of the patient also led to the diagnosis of non-mosaic Klinefelter syndrome, probably explaining the non-lethal and even rather minor phenotype compared to the rare affected males already described.