Skeletal dysplasias — formative SAQs

Question 1 (10 marks)

A term newborn develops severe respiratory distress in the delivery room. Examination reveals a very narrow chest, markedly short limbs, and a large head. A chest radiograph shows short horizontal ribs and a small bell-shaped thorax, and the long-bone films show short, curved femurs with flattened vertebral bodies. ^{[2] [5]}

(a) Give the most likely diagnosis, the molecular pathway involved, and the key prognostic implication. (3 marks) ^[2]

(b) Outline the immediate and perinatal management, including the decision point that governs escalation versus palliation. (3 marks) ^[5]

(c) Describe the recurrence-risk counselling for this couple and the reproductive options for a future pregnancy. (4 marks) ^[2]

Model answer

The most likely diagnosis is thanatophoric dysplasia, the commonest lethal skeletal dysplasia, caused by a gain-of-function variant in FGFR3 that is more severe than the variant of achondroplasia. The short curved (telephone-receiver) femurs, the narrow bell-shaped thorax with short horizontal ribs, the flattened vertebral bodies, and the large head are characteristic. The key prognostic implication is that this is a lethal dysplasia: the small thorax causes pulmonary hypoplasia, and death from respiratory failure occurs within hours to days of birth regardless of intervention. ^{[2] [5]}

The immediate management confirms the diagnosis at the bedside by the skeletal radiographs and involves the neonatal, genetic, and the family in a shared decision about the limits of intervention. Because intubation and ventilation cannot overcome the fixed pulmonary hypoplasia, management shifts to palliation focused on comfort rather than escalation once the lethal dysplasia is confirmed. The diagnosis is confirmed by molecular FGFR3 testing, and bereavement support is begun. ^[5]

The recurrence-risk counselling addresses the small gonadal mosaicism risk of a new dominant FGFR3 variant, which is lower than the twenty-five per cent recurrence of a recessive disorder but not negligible. Post-mortem molecular confirmation establishes the variant and enables targeted prenatal diagnosis by chorionic villus sampling or amniocentesis, or preimplantation genetic testing, in a future pregnancy. The family is referred to the clinical genetics service before the next pregnancy so that the options and the timing of prenatal diagnosis are understood in advance. ^[2]