Key Clinical Message
When you see a neonate with upper limb phocomelia, lower limb anomalies,
pulmonary hypoplasia, and central nervous system, cardiac, and
urogenital anomalies, you should examine an SF3B4 mutation.
Acrofacial dysostosis encompasses a heterogeneous group of disorders
characterized by craniofacial abnormalities resembling those observed in
mandibulofacial dysostoses such as Treacher-Collins syndrome as well as
additional limb and visceral anomalies. The well-known subtypes of
acrofacial dysostosis include Miller syndrome (postaxial acrofacial
dysostosis) and Nager syndrome (preaxial acrofacial dysostosis). The
former is associated with postaxial limb deficiency (postaxial defects
of all four limbs), whereas the latter is associated with preaxial limb
deficiency (radial ray deficiency and only minor involvement of the
great toes). Rodriguez syndrome is a lethal form of acrofacial
dysostosis associated with upper limb phocomelia, lower limb anomalies,
pulmonary hypoplasia, and central nervous system, cardiac, and
urogenital anomalies.1 However, it has been postulated
that Nager and Rodriguez syndromes are allelic disorders caused by
heterozygous mutations in the SF3B4 gene mapped on
1q21.2.2 Here, we report the case of a male neonate
whose manifestations were consistent with those of Rodriguez syndrome.
Molecular analysis revealed an SF3B4 mutation.
The affected neonate was delivered by emergent cesarean section due to
non-reassuring fetal status at 30 weeks and 3 days of gestation,
immediately after emergent maternal transport, because of premature
rupture of the membrane. Massive amniotic fluid leakage had occurred,
suggesting polyhydramnios. The birth weight was 1160 g. The Apgar score
was 5 at both 1 min and 5 min. At birth, the neonate was markedly
hypotonic, with feeble respiration. He also showed Treacher-Collins
syndrome-like facial features with severe micrognathia and phocomelia of
the upper limbs and absent thumbs (Figure 1A-C). He did not respond well
to resuscitation and passed away 1.5 hours after birth. Postmortem
radiography showed hypoplasia of the scapular wings, severely
hypoplastic, triangular-shaped humeri, elbow synostosis, radioulnar
hypoplasia, and absence of the first digits. The axial skeleton and
lower limbs were unremarkable. An autopsy performed after obtaining the
parentsā consent revealed severe post-ductal coarctation of the aorta
and bicuspid aortic valves, intrapelvic right kidney, and absent
lobulation of the left lung. The radial alveolar count was 3.0,
suggesting mild hypoplasia of the lung. Molecular analysis, DNA
extraction using PureLinkĀ® Genomic Kits, and Sanger sequencing ofSF3B4 revealed a heterozygous variant (c.1060dupC;
p.Arg354Profs*132).
The variant was previously reported to be pathogenic for Nager
syndrome.3, 4 However, severe upper limb defects,
association with multi-organ anomalies, and perinatal lethality in the
present case warranted a diagnosis of Rodriquez syndrome rather than
Nager syndrome. Our experience supports the notion that both types are
phenotypic variations of the same disorder.