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]

Question 2 (10 marks)

A two-year-old presents with rhizomelic shortening of the limbs, a large head with frontal bossing and midface hypoplasia, trident hands, genu varum, and normal development. Her parents, both of average stature, ask whether any treatment can increase her adult height, and the mother reports that she snores loudly and pauses in her sleep. [1]

(a) Give the diagnosis, the inheritance, and the likelihood that her parents are carriers. (3 marks) [1]

(b) Outline the disease-modifying therapy now available, its mechanism, and the evidence for its efficacy. (4 marks) [4]

(c) Explain the significance of the snoring and sleep pauses, and describe the surveillance this child needs over the next two years. (3 marks) [1]

Model answer

The diagnosis is achondroplasia, the commonest non-lethal skeletal dysplasia, caused by a gain-of-function variant in FGFR3. It is autosomal dominant, but around eighty per cent of cases arise as a new variant in the father's germ line, so the likelihood that her average-statured parents are carriers is very low; the recurrence risk is the small gonadal mosaicism risk of a new dominant variant rather than the twenty-five per cent of a recessive disorder. Intellect is normal, and the short stature is disproportionate. [1]

The disease-modifying therapy is vosoritide, a C-type natriuretic peptide analogue given as a once-daily subcutaneous injection. Vosoritide works by overriding the FGFR3 brake on chondrocyte proliferation at the growth plate, restoring the resting-to-proliferating transition that the gain-of-function variant had arrested. A randomised, double-blind, phase three placebo-controlled trial showed a sustained increase in annualised growth velocity in children with achondroplasia, establishing vosoritide as the first therapy directed at the underlying mechanism. It runs in parallel with, not instead of, multidisciplinary surveillance, because it does not address the complications of achondroplasia. [4]

The snoring and sleep pauses suggest sleep-disordered breathing, which in achondroplasia reflects midface hypoplasia and adenoidal hypertrophy, and — more dangerously — may signal foramen magnum stenosis with cervicomedullary compression, a cause of sudden unexpected death in achondroplastic infants. Over the next two years the surveillance includes a sleep study, a low threshold for MRI of the craniovertebral junction, syndrome-specific growth and head-circumference plotting, ENT and audiology review for the recurrent otitis media and conductive hearing loss, and developmental and psychosocial support. [1]