A case of timely prenatal testing of current pregnancy based on evaluating an index case with uncertain diagnosis.

Authors:Dr Sumitra Bachani,* Dr Suchandana Dasgupta ** * Professor & Senior Specialist,** NBE Fellow Maternal-Fetal Medicine Vardhman Mahavir Medical College & Safdarjung Hospital

Introduction: There are more than 400 known types of generalized skeletal dysplasia. The estimated prevalence is 2-7 in 10,000 live births.1 The genetic etiology of an increasing number of cases with skeletal dysplasia is now known, making an early diagnosis possible. In the case of a previously affected pregnancy witha definitive geneticdiagnosis,prenatal genetic testing can thenbe offered. Inheritance patterns can vary; therefore, Genetic counselling and appropriate Next-generationsequencing (NGS), such as Clinical exome or Whole exome sequencing (WES) modalities,help investigate affected pregnancies and arrive at a diagnosis.

We report such a case where a correct diagnosis of the proband facilitated a timely prenatal test in the subsequent pregnancy.

Clinical findings and relevant history: A 34 year G3P2L2 with 13 weeks of gestation presented with one affected female child of 7 years with a history of delayed dentition, inability to walk, multiple fractures, and bowing of both legs since she was 8 months old. (Fig 1A-1D) On investigation of the girl child’s serum calcium, phosphate, and parathyroid hormone (PTH) levels were normal, but alkaline phosphate (ALP) was high (336 IU/L). A bone biopsy was performed at 10 months of age, and the histopathological features were consistent with fibrous dysplasia. Magnetic Resonance Imaging (MRI) at one year of age revealed a fracture of the lower diaphysis of the femur with mild angulation. She underwent multiple surgeries for repeated fractures and later planned for deformity correction for bowing of her legs. However, no definitive diagnosis was made, and probable conditions like fibrous dysplasia, osteogenesis imperfecta and metabolic rickets were considered. She has another healthy male sibling of 10 years of age. It was consanguineous marriage, and all were spontaneous conceptions. Three generation pedigree was not significant

Fig 1A: Current photograph of index child; Fig 1B: X-ray (A.P. view) of bilateral pelvis with bilateral femur bowing and bilateral femur meta-diaphysis fracture (age 10 months); Fig 1C: X-ray (lateral view) showing anterolateral bowing of bilateral femur (age 10 months); Fig 1D: X-ray (A.P. view) showing left humerus bowing with fracture and crowding of ribs at 4 years of age

Diagnostic assessment: The current pregnancy was confirmed by ultrasound at 10 weeks gestation. A nuchal translucency scan was done at 12 weeks, and Non-Invasive Prenatal Screening (NIPS) was also done, which was low risk for aneuploidy. With genetic counselling and pretest counselling, the proband was offered Whole-exome sequencing (WES). The WES revealed that the proband was homozygous for pathogenic variant consistent with osteogenesis imperfecta type VI having autosomal recessive inheritance. (Fig2)

Fig 2: Whole Exome Sequencing of index child showing mutation of SERPINF1 gene.
At 17 weeks, amniocentesis was performed with Sanger sequencing, which revealed the fetus to be heterozygous for O.I. VI. (Fig 3). The couple were counselled post-test that the baby would not be affected but a disease carrier.


The couple was offered carrier screening, and both partners were detected to be heterozygous carriers for the same condition. (Fig 4)


Follow up and outcome: The Anomalyscan done at 18 weeks was normal, and follow up growth scans done at 32 and 36 weeks were also unremarkable. The mother had an uneventful labour and delivered a 3.1 kg male baby at term. The postnatal period was uneventful. The baby is of 9 months of age and doing well to date.

Discussion: Osteogenesis imperfecta (O.I.), also known as brittle bone disease, is a genetic disorder of connective tissues caused by an abnormality in the synthesis or processing of type I collagen. A total of 17 types of subgroups have been identified depending upon the genetic mutations.2

In the presence of consanguinity, autosomal recessive conditions shouldbe considered. Type VI mutation involvesthe SERPINF1 gene; characteristic histological presentation includes lamellar bone with fish scale pattern under a polarized light microscope and severe mineralization defects. It presents with moderate to severe skeletal manifestations, normal sclera, and absence of dental involvement.3 Byers et al. formulated a guideline for genetic evaluation in suspected cases of O.I.4 They suggested that if in the first year of life there are frequent unexplained fractures that are non-accidental, it may raise suspicion of O.I. On clinical examination, if an infant with unexplained fractures has few features of O.I., as may be the case with O.I. type I, IV, V and VI, it may be difficult to confirm or exclude the diagnosis based on the history of fractures, family history, and physical examination alone, particularly in the 0–8 months age group. Herein lies the role of genetic history and phenotype identificationin ascertaining the pathology.

Moldenhauer et al. reported two Brazilian families from a small city called Bueno Brandao in Southeast Brazil with a severe deforming form of autosomal recessive O.I., in which WES identified a novel 19-bp homozygous deletion in exon 8 of SERPINF1. All affected individuals in this study had their first fracture approximately at 1 year (except one who had their first fracture at 5 months). None of them had dentinogenesis imperfecta, and only one had mild blue sclera. All affected individuals had a homozygous 19-bp deletion in exon 8 of SERPINF1 (c.1152_1170del; p.384_390del)

In their study, Francis H et al. described 8 patients initially diagnosed with O.I. type IV who shared uniquecharacteristics. Fractures were first documented between 4 and 18 months of age.Patients with O.I. type VI sustained more frequent fractures than patients with O.I. type IV. Sclerae were white or faintly blue, and dentinogenesis imperfecta was uniformly absentAll patients had vertebral compression fractures and no radiological signs of rickets. Lumbar spine bone mineral density was low and similar to age-matched patients with O.I. type IV. Serum alkaline phosphatase levels were elevated compared with age-matched patients with type IV OI (4096145 U/litre versus 295695 U/litre; p<0.03 by t-test). Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations and type I collagen protein analyses were normal. They proposed to name this disorder “O.I. type VI.” &nsp;

Thus in the current case, the proband’s clinical presentation was not classical of O.I., and she had an unaffected sibling. Although there was a suspicion of O.I., no genetic counselling or confirmatory genetic tests were done. NIPS had been done, which was irrelevant and not cost-effective for this condition. It is essential to thoroughly investigate the affected case with appropriate tests. Otherwise, the window period for investigations and diagnosing the disease becomes narrow if the woman conceives again, as was in the current case. The couple was thus helped with the decision regarding the current pregnancy. Also, they were both detected to be the carriers and understood the need for prenatal tests in every pregnancy. The strength of the case workup was the timely assessment of the proband and the role of Genetic counselling and appropriate testing. The limitation is that we had to rely on WES to diagnose the condition as the presentation was not classical.


  1. Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet. 1986;23(4):328-32.
  2. Van Dijk FS, Byers PH, Dalgleish R, Malfait F, Maugeri A, Rohrbach M, et al. Best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta. Eur J Hum Genet. 2012;20:11–19.
  3. Subramanian S, Viswanathan VK. Osteogenesis Imperfecta. StatPearls; 2022.
  4. Byers P, Krakow D, Nunes M. et al. Genetic evaluation of suspected osteogenesis imperfecta (O.I.). Genet Med 2006;8:383–88.
  5. Moldenhauer Minillo R, Sobreira N, de Fatima de Faria Soares M, Jurgens J, Ling H, Hetrick K, et al. B: Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families. Mol Syndromol 2014;5:268-275.
  6. Glorieux, F.H., Ward, L.M., Rauch, F., Lalic, L., Roughley, P.J. and Travers, R. (2002), Osteogenesis Imperfecta Type VI: A Form of Brittle Bone Disease with a Mineralization Defect. J Bone Miner Res, 17: 30-38.
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