Table 3.

Genes of Interest in the Differential Diagnosis of Schmid Metaphyseal Chondrodysplasia

GeneDisorderMOIClinical Features of Disorder
Overlapping w/SMCDDistinguishing from SMCD
DNAJC21
EFL1
SBDS
SRP54 		Shwachman-Diamond syndrome AD
AR 1
  • Short stature
  • Metaphyseal widening & irregularities
  • Skeletal changes usually milder
  • Metaphyseal changes usually greatest in ribs
  • Extraskeletal features: exocrine pancreatic insufficiency, neutropenia, ↑ infections, anemia
MMP9 Metaphyseal anadysplasia, MMP9-related 2 (OMIM 613073)AR
  • Genu varum
  • Metaphyseal dysplasia
  • Short limbs, limb disproportion
  • Apparent in 1st few mos of life but resolves spontaneously w/age
  • Epiphyseal dysplasia
  • Generalized osteopenia
  • Normal stature by adolescence
MMP13 Metaphyseal anadysplasia, MMP13-related 2 (OMIM 602111)AD
  • Genu varum
  • Short limbs, limb disproportion
  • Severe metaphyseal changes in long bones (irregularities, widening, marginal blurring)
  • Apparent in 1st few mos of life but resolves spontaneously w/age
  • Epiphyseal dysplasia
  • Generalized osteopenia
  • Normal stature by adolescence
Metaphyseal dysplasia Spahr, MMP13-related 2 (OMIM 250400)AR
  • Genu varum
  • Metaphyseal dysplasia
  • Moderate short stature
  • Abnormal ribs
  • Carpal bone hypoplasia
  • Iliac crest irregularity in childhood
PTH1R
(PTHR1)		Metaphyseal dysplasia, Jansen type, PTH1R-related 2 (OMIM 156400)AD
  • Genu varum
  • Short stature
  • Metaphyseal dysplasia
  • Waddling gait
  • ± dysmorphic features: prominent superciliary arches, exophthalmos
  • Hypercalcemia, hypercalciuria
  • Metaphyseal changes more severe
  • Sclerosis of skull in late adulthood
RMRP Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia, McKusick type), RMRP-related 2 (OMIM 250250)AR
  • Genu varum
  • Short-limbed short stature
  • Variable metaphyseal dysplasia
  • Coxa vara rarely seen
  • Extraskeletal features: fine/sparse hair, immune dysfunction, transient macrocytic anemia, Hirschsprung disease
  • Ligament laxity
RUNX2 Metaphyseal dysplasia w/maxillary hypoplasia, RUNX2-related 2 (OMIM 156510)AD
  • Metaphyseal flaring of long bones
  • Short stature
  • Broad clavicles
  • Maxillary hypoplasia
  • Variable brachydactyly

AD = autosomal dominant; AR = autosomal recessive; SMCD = Schmid metaphyseal chondrodysplasia; MOI = mode of inheritance

1.

Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in DNAJC21, EFL1, or SBDS is inherited in an autosomal recessive manner. SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner.

2.

Terminology per 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023]

From: Schmid Metaphyseal Chondrodysplasia

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Adam MP, Feldman J, Mirzaa GM, et al., editors.
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