Table 2.

Genes of Interest in the Differential Diagnosis of Cleidocranial Dysplasia Spectrum Disorder

Gene / Genetic
Mechanism		DisorderMOICraniofacial & Dental FeaturesSkeletal FeaturesOther Features
ALPL Hypophosphatasia 1AR
AD 2
  • Children w/infantile form may present w/very poorly mineralized cranium & widened cranial sutures.
  • Premature deciduous tooth loss
  • Generalized defect of mineralization w/delayed ossification of multiple skeletal elements
  • Children w/infantile form may present w/short ribs & narrow thorax.
  • Clavicles least affected
  • Rachitic skeletal changes
  • Very low alkaline phosphatase activity in serum & tissues
  • Nephrocalcinosis
  • Hypercalcemia
CBFB
(intragenic pathogenic variants)		CBFB-related CCD (OMIM 620099)AD
  • Delayed closure of fontanelle
  • Delayed/absent eruption of deciduous teeth
  • Supernumerary teeth
  • Hypoplastic or absent clavicles, clavicula bipartita
  • Metacarpal/metatarsal pseudoepiphyses
  • Delayed ossification of pubic & carpal bones
  • Short distal phalanges
  • Normal stature
  • DD (mild to moderate)
CBFB
(16q22.1 deletions involving CBFB)		Chromosome 16q22 deletion syndrome (OMIM 614541)ADWide-open fontanelles
  • Short clavicles 3
  • Short stature
  • Short distal phalanges
  • Delayed ossification of skull
  • Poor weight gain
  • DD
  • Congenital heart defect
CTSK Pycnodysostosis ARFailure of closure of cranial sutures w/persistence of open fontanelles
  • Acro-osteolysis
  • Osteopetrosis; radio-opacity of all bones ↑ due to ↑ density of trabecular bone but not cortices
  • Short stature w/↑ bone fragility, short terminal phalanges
FIG4 Yunis Varon syndrome (OMIM 216340)AR
  • Wide-open fontanelles & sutures
  • Unusual mineralization of skull
  • Hypoplastic clavicles
  • Absence/hypoplasia of thumbs, halluces, & distal phalanges
  • Gracile bones
  • Prenatal growth deficiency
  • Brain malformations
LMNA
ZMPSTE24 		Mandibuloacral dysplasia (OMIM PS248370)AR
  • Delayed closure of cranial sutures
  • Micrognathia
  • Early tooth loss
  • Dysplastic clavicles
  • Acro-osteodysplasia of fingers & toes w/delayed ossification of carpal bones
  • Progressively stiff joints
  • Short stature
  • Alopecia; scalp hair sparse by 3rd decade
  • Atrophic skin w/↓ subcutaneous fat
  • Skin hyperpigmentation
MSX2
(intragenic pathogenic variants)		Parietal foramina w/CCD 4AD
  • Enlarged parietal foramina
  • Broad forehead w/frontal bossing
  • Not assoc w/dental abnormalities
Clavicular hypoplasia
MSX2
(microduplications upstream of MSX2)		MSX2-related CCD w/synpolydactyly 5ADPhenocopy of CCDPhenocopy of CCDSynpolydactyly in some

AR = autosomal recessive; AD = autosomal dominant; CCD = cleidocranial dysplasia; DD = developmental delay; MOI = mode of inheritance

1.

In one report, an individual with severe CCD was initially thought to have hypophosphatasia [Unger et al 2002].

2.

Perinatal and infantile hypophosphatasia are typically inherited in an autosomal recessive manner. The milder forms, especially adult hypophosphatasia and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner depending on the effect that the ALPL pathogenic variant has on TNSALP activity.

3.
4.
5.

From: Cleidocranial Dysplasia Spectrum Disorder

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