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Two siblings from a consanguineous Lebanese family presenting with skeletal and ocular abnormalities were investigated. For both, delivery was normal, with no recall of exposure to pre- or perinatal environmental toxins.

Patient 1: The first affected girl, IV-4, is the fourth child in the family and was born at term from a 28-year-old mother and a 32-year-old father. At birth, her length was 53 cm (+0.7 SD) and her weight was 4000 g (+1.3 SD). Major complaints noted by the parents during her early development included recurrent episodes of constipation, bad urine smell, growth retardation, and developmental delay. The patient started walking without help at the age of 2 and a half years, although with some stepping, and talked more or less clearly by age 3. At around age 3, fractures happened recurrently after minor traumas, treated accordingly by cast and pins. At age 4, the patient received bisphosphonates treatment through pamidronate infusions, which improved bone mineral density and fracture frequency without reshaping the compression fractures. The latter treatment was discontinued by the parents after 5 months due to the limited availability of the drug in the local market, especially since the fracture recurrence had been reduced, albeit not completely resolved.

At the age of 6, a bilateral cataract was found during a routine ophthalmological examination and treated by cataract extraction with posterior chamber intraocular lens implantation and anterior vitrectomy in both eyes (OU).

When first seen by us at the age of 12 years, the patient was cooperative and could understand orders. Moderate intellectual disability was observed. Her head circumference (OFC) was 53 cm (0 SD), her height 126.5 cm (<−2.3 SD), and her weight 28 kg (<−2.3 SD). She had long palpebral fissures with long eyelashes; translucent teeth; thin lips; short and webbed neck; short trunk; kyphoscoliosis; increased inter-nipples distance; pectus carinatum; truncal obesity; flat feet; joint laxity; and one small café-au-lait spot on her lower back. External genitalia exam was normal with no pubertal signs. Visual acuity could not be assessed. Eye examination revealed the presence of thin cornea. Color vision by Ishihara plates was normal OU. Pupils were equal, round, and reactive with no afferent pupillary defect OU. Intraocular pressure was normal (13 mmHg) OU. Cover-uncover test showed a 20 prism diopters exotropia at near and distance with no pattern, alternating fixation, and horizontal nystagmus. Ductions and versions showed limited elevation, depression, and adduction of the right eye (OD), and full motility in the left eye (OS). Anterior segment exam showed a clear conjunctiva, white sclera, clear thin corneas (central corneal thickness of 346 µm OD and 343 µm OS; average central corneal thickness for age 343 µm is around 555 µm) with normal horizontal diameter (white-to-white, 10.87 mm OD and 11.83 Mm OS), deep and quiet anterior chamber OU, normal irides, PCIOL in place OU. Funduscopic exam showed a clear vitreous OU, optic discs with large cups but healthy rims, normal vasculature, and normal macula and periphery. Neurological and cardiac evaluations were unremarkable. A brain MRI was performed but did not yield any remarkable findings. A review of a skeletal survey performed throughout the years to assess the recurrent fractures revealed thinning of the occipital bone; multilevel flattening and biconcave compression of the vertebra mostly flattened at L1/L5; a scoliosis; a left coxa valga; a non-displaced transverse fracture of the mid diaphysis of the left radius and ulna that was stabilized with pins; healed spiral fractures of the mid third of the diaphysis on the left and right femurs with residual angulation and mild bowing of the left femur; comminuted fracture of the distal third of the diaphysis of the left femur with displacement; and bone demineralization and horizontal sclerotic stripes on both tibia and fibula (Figure 1). Assessment of bone density showed a Z-score of −4.88.

Patient 2: Subject 2, a girl born 7 years after her affected sister, was seen at the age of 5 years. At birth, her length was 47 cm (−1.6 SD), and her weight was 3300 g (O SD). The parents noticed the same manifestations as her sister, including developmental delay, constipation, bad urine smell, and multiple fractures secondary to minor traumas in addition to a more prominent pectus carinatum. At the time of her examination, her OFC was 51 cm (O SD), her length was 83 cm (<−2.3 SD), and her weight was 11 Kg (−2 SD). She had the same clinical manifestations as her affected sister, in addition to a tide tongue and hyperextensible hip joints (Supplementary Table S1). External genitalia, neurological and heart examinations, as well as echocardiography and brain MRI were unremarkable. Ophthalmological examination revealed the presence of bilateral cataract with horizontal nystagmus. Analysis of her X-rays showed the presence of horizontal sclerotic stripes related to mineralization disorders; flattening of the vertebral body of the lower dorsal and lumbar vertebra; anterior wedge compression fracture of L1; biconcave flattening of L3; a healed subacute angulated fracture of the distal third of the left femoral diaphysis with sclerotic borders; a per-trochanteric impacted fracture of the left femoral neck; another angulated fracture of the distal diaphysis at the junction with the metaphysis; and a healed spiral fracture of the distal third of the diaphysis with bone remodeling (Figure 2).

Examination of the parents and their non-affected children showed a complete absence of all the features present in the affected siblings. A detailed family history revealed that two children (IV-5 and IV-6) died shortly after birth without any identified medical reason according to the parents.

WES was performed in the patient IV-4 and led to the identification of approximately 97,866 variants. Considering the recessive inheritance of the disease in the pedigree and consanguinity, Researchers assumed identity by descent and thus selected homozygous variants. This led to the selection of 36,903 variants. Additional filtering was then performed to exclude all non-genic, non-splice site, and intronic variants as well as all frequent variants (present in more than 1% in databases). This filtering strategy led to the selection of a list of 117 variants that were thoroughly studied in order to select the candidate variants that can explain the clinical picture of the patient. One homozygous variant, the p.Tyr414* (c.1242C>A) in XYLT2 (NM_022167.3), was considered as the only candidate variant based on the gene function. Sanger sequencing confirmed the presence of this mutation at a homozygous state in both affected patients (Figure 3) and at heterozygous state in the parents. The identified variant in the XYLT2 gene is also absent in the local database and in gnomAD.

The selected variant is located in exon 6 of XYLT2 and is predicted to be pathogenic by different pathogenic prediction tools ^[1]. It is classified as likely pathogenic (Class IV: PVS1 and PM2) based on the ACMG classification ^[1][2]. Indeed, the variant meets the criteria PVS1, since it is a nonsense variant in a gene where loss of function is a known mechanism causing a disease. It also meets the criteria PM2, because it is absent from control databases including the in-house database.