Rickets manifestations in a child with metaphyseal anadysplasia, report of a spontaneously resolving case

Abstract

Introduction: Rickets is not an unusual diagnosis for pediatricians even currently in developed countries. Children typically present with leg bowing, enlargement of wrists, rachitic rosary (swelling of costochondral junctions) and/or waddling gait. But not every child with growth delay and enlarged metaphyses is diagnosed with rickets. Metaphyseal anadysplasia (MAD) is a disorder of variable severity with metaphyseal flaring and irregularities, without vertebral abnormalities. MAD is characterized by an early onset and a regressive course in late childhood without treatment, despite persistent short stature. Autosomal dominant or recessive variants in the matrix metalloproteinase 13 gene (MMP13) are responsible for these transient metaphyseal changes.

Case presentation: We report a new pathogenic heterozygous variant in MMP13 (NM_002427.4: c.216G>C, p.Gln72His) in a toddler, initially thought to have rickets, and his father, with MAD phenotypes. Additionally, we review the seven reported MMP13 variants.

Conclusion: One should keep a wide differential diagnosis in cases of suspected rickets, including skeletal dysplasias which might have a regressive course.

Keywords: Autosomal dominant variant; Metaphyseal anadysplasia; Regressive course; Rickets mimicking presentation disease.

Fig. 1

Familial pedigree. Our proband (III-1) and father (II-2) have the described variant c.216G > C;p.Gln72His. Proband’s uncle (II-1), and two of the paternal grandmother’s sisters (I-3 & I-4) may be also affected because of short adult stature but were not evaluated clinically or molecularly

Fig. 2

 a Proband’s chest X-ray, at 18 months-old, revealing widening and irregularities of humeral metaphyses along with cupping and enlargement of anterior costochondral junctions. b Proband’s hip X-ray at 24 months with cupiliform aspect of femoral neck. c & d Proband’s knee X-ray at 18 months-old revealing fine-tooth-comb irregularities and widening of metaphyses

Fig. 3

MMP13 protein structure and its 3 different domains: binding, catalytic and hemopexin-like. a The numbers correspond to the different exons. Known pathogenic variants are drawn in their location in the protein, according to inheritance pattern. There are 7 missense variants, including the one described in this paper and 1 nonsense variant. b A schematic diagram of MMP13 3D protein structure, the 5 pathogenic variants leading to MAD type 1 are between aa 71 and 75, in the binding domain. Model done with The Phyre2 web portal [20], representation done with Chimera [21].