Short Stature With Microcephaly And Distinctive Facies

A number sign (#) is used with this entry because of evidence that short stature with microcephaly and distinctive facies is caused by homozygous mutation in the CRIPT gene (604594) on chromosome 2p21.

Description

Short stature with microcephaly and distinctive facies is characterized by pre- or postnatal growth retardation, frontal bossing, high forehead, sparse hair and eyebrows, and telecanthus. Patients also show skin dyspigmentation, with hyper- and/or hypopigmented areas (Leduc et al., 2016).

Clinical Features

Shaheen et al. (2014) studied 2 unrelated Saudi Arabian boys with height and weight more than 3 SD below the mean at birth and persistent growth deficiency postnatally, which the authors designated 'primordial dwarfism.' The boys also exhibited distinctive facial dysmorphism that did not appear to fit any known syndrome and involved frontal bossing, high forehead, sparse hair and eyebrows, telecanthus, mild proptosis, anteverted nares, and flat nasal bridge. Postnatally, the boys' lengths were -4.2 SD and -5 SD below the mean for age and gender, and both patients had microcephaly, with head circumferences at least 2.5 SD below the mean. Additional skeletal features included hypoplastic terminal phalanges with brachydactyly, osteopenia, and talipes equinovarus. Both patients had ocular abnormalities: one was blind and the other showed albinoid fundus with markedly impaired retinal function. One patient also had hypopigmented skin patches. Brain MRI showed bifrontal subdural hygroma in 1 patient who had profound global developmental delay at age 3 years; in the other, who died at 2 months of age, there was increased white matter signal and hypogenesis of corpus callosum. The patient who died had recurrent infections and persistent anemia with anisopoikilocytosis.

Leduc et al. (2016) reported a 4-year-old African American girl with postnatal growth retardation, microcephaly, dysmorphic features, and pigmentary abnormalities. Although she had normal birthweight and length, she showed failure to thrive in infancy, with growth parameters below the 5th centile. At age 7 months, she was diagnosed with high myopia, intermittent exotropia, and latent nystagmus; optic discs were normal and there was no evidence of retinopathy. Examination at age 4 years revealed persistent short stature and low weight as well as microcephaly. She had significant language delay and complex partial seizures, but brain MRI was unremarkable. Dysmorphic features included frontal bossing, high forehead, sparse hair and eyebrows, telecanthus, long and flat philtrum, and retromicrognathia. Skeletal features included proximally placed thumbs and syndactyly of 4-5 toes bilaterally; x-rays showed bilateral hindfoot valgus and forefoot abduction, with lateral subluxation of the tarsal navicular bones. She also had mixed hyper- and hypopigmented macules on the face, arms, and legs as well as hyperkeratotic follicular papules on her cheeks and arms.

Molecular Genetics

In a 3-year-old Saudi Arabian boy with short stature, microcephaly, and distinctive facial dysmorphism, Shaheen et al. (2014) performed exome sequencing and identified homozygosity for a 2-bp insertion in the CRIPT gene (604594.0001) that was present in heterozygosity in his first-cousin unaffected parents. An affected sister was deceased. In the first-cousin Saudi Arabian parents of an unrelated deceased male infant with short stature and microcephaly, who shared the highly characteristic facial appearance of the 3-year-old boy, Shaheen et al. (2014) identified heterozygosity for a 1-bp deletion in CRIPT (604594.0002). An affected brother was deceased.

By whole-exome sequencing and chromosomal microarray in a 4-year-old African American girl with postnatal growth retardation, microcephaly, dysmorphic features, and pigmentary abnormalities, Leduc et al. (2016) identified compound heterozygosity for mutations involving the CRIPT gene: a missense mutation (C3Y; 604594.0003) and a 1.3-kb deletion (604594.0004), each inherited from an unaffected parent.