Clinical and Molecular Diagnosis of Osteocraniostenosis in Fetuses and Newborns: Prenatal Ultrasound, Clinical, Radiological and Pathological Features

Abstract

Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of FAM111A associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS.

Keywords: FAM111A; Kenny-Caffey syndrome (KCS); asplenia; cloverleaf skull; gracile bone dysplasia; hypoplastic spleen; microphthalmia; osteocraniostenosis (OCS).

Figure 1

Clinical case #1. (A1–4) Frontal bossing, bitemporal narrowing with supra-auricular bulging and parietal bossing, short palpebral fissures, hypertelorism, narrow mouth, low-set ears. (A5–8) Camptodactyly of proximal interphalangeal joints of the 2nd–5th fingers. (A9) Bilateral short hallux. (A10) Micropenis. (B) Babygram X-rays: underossification of the skull, 11 pairs of thin ribs, mild platyspondyly, mild irregular cervical vertebrae, thin long bones with increased density, metaphyseal flaring and with obliteration of the medullary cavity. (C,D) Pathological examination of femur: (C1) macroscopically, the femur had a thin diaphysis with splayed metaphyses, and appeared similar to the picture (D) originally presented by Unger et al. [7]. (C2) Histological examination: architecture of the growth plate of the proximal femur showing a normal resting cartilage (R), a rarefied proliferating zone (P) and narrow cartilage lacunae in the hypertrophic zone (H). Scale bar = 25 μm.

Figure 2

Clinical case #2: whole-body X-rays. (A–E) Reduced long bone length, thin long bones, bilateral femoral fractures with bowing. (F,G) Fractures with deformity of the left radius and ulna. (A,B,F,G) Gracile and irregular ribs, with fractures. (C,F,G) Bowing of the fibula and ulna. (B–G) Enlarged metaphyses of the tibia, femora and humeri.

Figure 3

Scheme of the FAM111A protein and known pathogenic variants associated with either osteocraniostenosis (OCS, top) or Kenny-Caffey syndrome (KCS, bottom). Cys485Phe was reported in [33], Ser541Tyr/Pro were reported in [5,32], respectively, Tyr562Ser was reported in [21], while all other variants were observed at the Laboratory of Genetics at CHUV ([7] and this report). The domain in orange has homology to trypsin-like peptidases, including an untested catalytic triad purportedly composed of Ser541/His385/Asp439 (red bars).